Transdermally absorbable base material containing lipid peptide compound

ABSTRACT

A transdermally absorbable base material including: a lipid peptide compound including at least one of compound of Formula (1) below and the similar compounds or pharmaceutically usable salts thereof; a surfactant; a specific polyhydric alcohol; a fatty acid; and water, 
                         
wherein R 1  is a C 9-23  aliphatic group; R 2  is a hydrogen atom or a C 1-4  alkyl group that optionally has a branched chain having a carbon atom number of 1 or 2; R 3  is a —(CH 2 ) n —X group; n is a number of 1 to 4; and X is amino group, guanidino group, —CONH 2  group, or a 5-membered cyclic group optionally having 1 to 3 nitrogen atoms, a 6-membered cyclic group optionally having 1 to 3 nitrogen atoms, or a condensed heterocyclic group constituted by a 5-membered cyclic group and a 6-membered cyclic group which optionally have 1 to 3 nitrogen atoms.

This is a Division of application Ser. No. 15/546,944 filed Jul. 27,2017, which in turn is a National Stage Application of Application No.PCT/JP2016/052488 filed Jan. 28, 2016, which claims the benefit ofJapanese Application No. 2015-014772 filed Jan. 28, 2015. The disclosureof the prior applications is hereby incorporated by reference herein inits entirety.

TECHNICAL FIELD

The present invention relates to a transdermally absorbable basematerial that contains a lipid peptide compound and is useful as a basematerial for transdermally absorbable formulation, and preferablyrelates to a stick-shaped transdermally absorbable base material and apremix for the transdermally absorbable base material.

BACKGROUND ART

Administration of active ingredients through transdermal absorption hasadvantages, such as being noninvasive and adjustable in amount of dose,and therefore is a widely employed approach, as well as oraladministration and injection administration. Transdermally absorbableformulation generally employs an approach of blending a transdermalabsorption enhancer with a transdermally absorbable base material inorder to enhance absorption of the active ingredients.

In recent years, attention has been paid to application of a gelledsubstance using a microemulsion technology to the transdermallyabsorbable formulation, from the viewpoint that the active ingredientsand the transdermal absorption enhancer having differenthydrophilicity/hydrophobicity can be simultaneously blended, and thatsolubility and activity of the active ingredients can be expected to beimproved. For example, a w/o microemulsion gel containing lecithin[Non-Patent Documents 1 and 2] and an o/w microemulsion gel containing athickener, such as a carboxy polymer or xanthan gum, [Non-PatentDocument 3] have been developed.

Hydrogels are useful as highly biocompatible gels because of using wateras a medium, and are used in a wide range of fields, typically for dailycommodities, such as paper diapers, cosmetics, and aromatic materials.

Examples of conventional hydrogels include polymer gels that are formedin such a manner that polymer chains are cross-linked to form athree-dimensional net structure, which in turn forms a noncovalent bondwith a medium, such as water, and swells. In recent years, hydrogelseach formed by self-assembly of a relatively low-molecular-weightorganic compound have been found, and studied in various ways. Manydevelopments have been made so far on low-molecular gelators that areamphiphilic compounds in each of which a long-chain alkyl group as ahydrophobic moiety is combined with a hydrophilic moiety. Examples ofsuch low-molecular gelators include one in which the hydrophilic moietyis amino acid [Non-Patent Document 4], one in which the hydrophilicmoiety is a peptide [Patent Documents 1 and 2], one in which thehydrophilic moiety is a monosaccharide or a polysaccharide [Non-PatentDocuments 5 and 6], and one in which the hydrophilic moiety is a polyol[Non-Patent Document 7]. A low-molecular gelator has also been developed[Non-Patent Document 8] by using the fact that a peptide formed ofvaline easily takes a 3-sheet structure.

PRIOR ART DOCUMENTS Patent Documents

-   Patent Document 1: International Publication No. 2009/005151    pamphlet-   Patent Document 2: International Publication No. 2009/005152    pamphlet Non-Patent Documents-   Non-Patent Document 1: S. Murdan, Expert Opin. Drug Deliv. 2(3),    489-505 (2005)-   Non-Patent Document 2: S. Kantaria, G. D. Rees, and M. J.    Lawrence, J. Controlled Release, 60, 355-365 (1999)-   Non-Patent Document 3: H. Chen, X. Chang, D. Du, L. Li, H. Xu,    and X. Yang, International J. Pharm., 315, 52-58 (2006)-   Non-Patent Document 4: Suzuki Masahiro, Yumoto Mariko, Kimura    Mutsumi, Shirai Hirofusa, and Hanabusa Kenji, Chemistry Letters, 33    (11), 1496-1497-   Non-Patent Document 5: Jong Hwa Jung, Georeg John, Mitsutosish    Mausda, Kaname Yoshida, Seiji Shinnkai, and Toshimi Shimizu    Langumuir, 2001, 17, 7229-7232-   Non-Patent Document 6: I. Hamachi, S. Kiyonaka, S. Shinkai,    Tetrahedron Lett., 2001, 42, 6141. I. Hamachi, S. Kiyonaka, S.    Shinkai, Chem, Commun., 2000, 1281-   Non-Patent Document 7: Masahiro Suzuki, Sanae Owa, Hirofusa Shirai,    and Kenji Hanabusa, Tetrahedron, 2007, 63, 7302-7308-   Non-Patent Document 8: Yoko Matsuzawa, Katsuyuki Ueki, Masaru    Yoshida, Nobuyuki Tamaoki, Tohru Nakamura, Hideki Sakai, and    Masahiko Abe, Adv. Funct. Mater., 2007, 17, 1507-1514

SUMMARY OF THE INVENTION Problem to be Solved by the Invention

Lots of the w/o and o/w microemulsion gels developed so far use apolymer compound as the gelator, and it has been pointed out thatapplying such gels to skin can cause stickiness or uneven spread(residue of the polymer compound) after a lapse of time.

If the transdermally absorbable formulation using the above-describedmicroemulsion gel is applied to the skin, the transdermal absorbabilityof the active ingredients is also an issue.

It is an object of the present invention to provide a noveltransdermally absorbable base material that uses a low-molecular gelatorto improve not only a sense of use, but also the transdermalabsorbability.

Means for Solving the Problem

As a result of intensive studies to solve the above problem, the presentinventors have found that a base material useful as the transdermallyabsorbable base material expected to increase the amount of penetrationof the active ingredients to the skin is provided by employing, as thetransdermally absorbable base material, an aqueous gel obtained byblending together a lipid peptide compound serving as a gelatorconstituted by a low-molecular lipid peptide or a pharmaceuticallyusable salt thereof, a surfactant, a specific polyhydric alcohol, and afatty acid, and thus completed the present invention.

Specifically, the present invention relates to, as a first aspect, atransdermally absorbable base material comprising a lipid peptidecompound including at least one of compounds of Formulae (1) to (3)below or pharmaceutically usable salts thereof, a surfactant,1,2-alkanediol or glycerin, at least one fatty acid, and water.

(wherein R¹ is a C₉₋₂₃ aliphatic group; R² is a hydrogen atom or a C₁₋₄alkyl group that optionally has a branched chain having a carbon atomnumber of 1 or 2; R³ is a —(CH₂)_(n)—X group; n is a number of 1 to 4;and X is amino group, guanidino group, —CONH₂ group, or a 5-memberedcyclic group optionally having 1 to 3 nitrogen atoms, a 6-memberedcyclic group optionally having 1 to 3 nitrogen atoms, or a condensedheterocyclic group constituted by a 5-membered cyclic group and a6-membered cyclic group which optionally have 1 to 3 nitrogen atoms.)

(wherein R⁴ is a C₉₋₂₃ aliphatic group; R⁵ to R⁷ are each independentlya hydrogen atom, a C₁₋₄ alkyl group that optionally has a branched chainhaving a carbon atom number of 1 or 2, or —(CH₂)_(n)—X group; n is anumber of 1 to 4; and X is amino group, guanidino group, —CONH₂ group,or a 5-membered cyclic group optionally having 1 to 3 nitrogen atoms, a6-membered cyclic group optionally having 1 to 3 nitrogen atoms, or acondensed heterocyclic group constituted by a 5-membered cyclic groupand a 6-membered cyclic group which optionally have 1 to 3 nitrogenatoms.)

(wherein R⁸ is a C₉₋₂₃ aliphatic group; R⁹ to R¹² are each independentlya hydrogen atom, a C₁₋₄ alkyl group that optionally has a branched chainhaving a carbon atom number of 1 or 2, or —(CH₂)_(n)—X group; n is anumber of 1 to 4; and X is amino group, guanidino group, —CONH₂ group,or a 5-membered cyclic group optionally having 1 to 3 nitrogen atoms, a6-membered cyclic group optionally having 1 to 3 nitrogen atoms, or acondensed heterocyclic group constituted by a 5-membered cyclic groupand a 6-membered cyclic group which optionally have 1 to 3 nitrogenatoms.)

The present invention relates to, as a second aspect, the transdermallyabsorbable base material according to the first aspect, in which thelipid peptide compound is a compound of Formula (1), wherein R¹ is alinear aliphatic group having a carbon atom number of 15; R² is ahydrogen atom; and R³ is 4-imidazole methyl group.

The present invention relates to, as a third aspect, the transdermallyabsorbable base material according to the first or second aspect, beingstick-shaped.

The present invention relates to, as a fourth aspect, the transdermallyabsorbable base material according to any one of the first to thirdaspects, further comprising at least one oleaginous base material.

The present invention relates to, as a fifth aspect, the transdermallyabsorbable base material according to any one of the first to fourthaspects, further comprising at least one organic acid.

The present invention relates to, as a sixth aspect, the transdermallyabsorbable base material according to any one of the first to fifthaspects, comprising, as the surfactant, at least one compound selectedfrom the group consisting of ethylene glycol alkyl ethers, phospholipid,and polyglycerin fatty acid esters.

The present invention relates to, as a seventh aspect, the transdermallyabsorbable base material according to any one of the first to sixthaspects, further comprising polyoxyethylene (20) sorbitan monolaurate(CAS registry number 9005-64-5) as a surfactant.

The present invention relates to, as an eighth aspect, the transdermallyabsorbable base material according to any one of the first to seventhaspects, in which the fatty acid is stearic acid.

The present invention relates to, as a ninth aspect, the transdermallyabsorbable base material according to any one of the fifth to eighthaspects, in which the organic acid is at least one selected from thegroup consisting of oxalic acid, citric acid, and ascorbic acid.

The present invention relates to, as a tenth aspect, the transdermallyabsorbable base material according to any one of the first to ninthaspects, being used for cosmetics or pharmaceutical products.

The present invention relates to, as an eleventh aspect, a premix for atransdermally absorbable base material, the premix comprising a lipidpeptide compound including at least one of compounds of Formulae (1) to(3) below or pharmaceutically usable salts thereof, a surfactant,1,2-alkanediol or glycerin, and at least one fatty acid.

(wherein R¹ is a C₉₋₂₃ aliphatic group; R² is a hydrogen atom or a C₁₋₄alkyl group that optionally has a branched chain having a carbon atomnumber of 1 or 2; R³ is a —(CH₂)_(n)—X group; n is a number of 1 to 4;and X is amino group, guanidino group, —CONH₂ group, or a 5-memberedcyclic group optionally having 1 to 3 nitrogen atoms, a 6-memberedcyclic group optionally having 1 to 3 nitrogen atoms, or a condensedheterocyclic group constituted by a 5-membered cyclic group and a6-membered cyclic group which optionally have 1 to 3 nitrogen atoms.)

(wherein R⁴ is a C₉₋₂₃ aliphatic group; R⁵ to R⁷ are each independentlya hydrogen atom, a C₁₋₄ alkyl group that optionally has a branched chainhaving a carbon atom number of 1 or 2, or —(CH₂)_(n)—X group; n is anumber of 1 to 4; and X is amino group, guanidino group, —CONH₂ group,or a 5-membered cyclic group optionally having 1 to 3 nitrogen atoms, a6-membered cyclic group optionally having 1 to 3 nitrogen atoms, or acondensed heterocyclic group constituted by a 5-membered cyclic groupand a 6-membered cyclic group which optionally have 1 to 3 nitrogenatoms.)

(wherein R⁸ is a C₉₋₂₃ aliphatic group; R⁹ to R¹² are each independentlya hydrogen atom, a C₁₋₄ alkyl group that optionally has a branched chainhaving a carbon atom number of 1 or 2, or —(CH₂)_(n)—X group; n is anumber of 1 to 4; and X is amino group, guanidino group, —CONH₂ group,or a 5-membered cyclic group optionally having 1 to 3 nitrogen atoms, a6-membered cyclic group optionally having 1 to 3 nitrogen atoms, or acondensed heterocyclic group constituted by a 5-membered cyclic groupand a 6-membered cyclic group which optionally have 1 to 3 nitrogenatoms.)

Effects of the Invention

A transdermally absorbable base material of the present inventionemploys a composition of an aqueous gel containing a gelator (lipidpeptide compound), a surfactant, a specific polyhydric alcohol, and afatty acid so as to be useful as a transdermally absorbable basematerial that is excellent in the transdermal absorbability thereof whenactive ingredients, such as hyaluronic acid, are blended therewith.

The lipid peptide compound contained in the transdermally absorbablebase material of the present invention is a very safe artificiallow-molecular compound constituted by only fat and peptides. Thecompound can form an aqueous gel without using, for example, across-linking agent that is needed for forming a conventionallydeveloped synthetic polymer gel, and consequently does not causeproblems, such as residual unreacted substances, including, for example,an unreacted cross-linking agent in the obtained transdermallyabsorbable base material.

Moreover, various ingredients contained as additives in thetransdermally absorbable base material of the present invention areadditives generally used as additives for foods, cosmetics, andpharmaceutical products.

That is, the transdermally absorbable base material of the presentinvention has high biological safety, and is very useful for theapplications described above, in particular, from the viewpoint of highsafety required for materials for, for example, medical or cosmetic use.

Furthermore, the transdermally absorbable base material of the presentinvention is expected be a base material that gives a high coolingsensation and spreads well without being folded or deformed when appliedto human skin or the like, and therefore is very useful as a basematerial for cosmetics or pharmaceutical products, and in particular, asa stick-shaped transdermally absorbable base material.

In addition, the present invention can provide a premixed raw materialsuitable for the transdermally absorbable base material described above.

Using the premix mentioned above allows the present invention to providethe transdermally absorbable base material in a gel state suitable forthe stick-shaped base material, particularly even if an organic acid,such as ascorbic acid, is blended in a large amount.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagram illustrating amounts of fluorescently-labeledhyaluronic acid in extracted solutions of skin after a skin permeabilitytest (Example 5) conducted using transdermally absorbable base materials(gels) prepared in Examples 2 to 4 and Comparative Example 1.

FIG. 2 is a conceptual diagram of a device used in the skin permeabilitytest in Example 5.

FIG. 3 is a diagram illustrating amounts of fluorescently-labeledinsulin (fluorescence intensities in μg/cm²) in extracted solutions ofthe skin after the skin permeability test (Example 8) conducted usingtransdermally absorbable base materials (gels) prepared in Examples 6and 7 and Comparative Example 2.

FIG. 4 is a diagram illustrating amounts of fluorescently-labeledinsulin (fluorescence intensities in μg/cm²) in extracted solutions oftapes obtained by tape stripping after the skin permeability test(Example 9) conducted using the transdermally absorbable base materials(gels) prepared in Examples 6 and 7 and Comparative Example 2.

FIG. 5 is a diagram illustrating amounts of fluorescently-labeledinsulin (fluorescence intensities in μg/cm²) in extracted solutions ofthe skin after the skin permeability test (Example 12) conducted usingtransdermally absorbable base materials (gels) prepared in Examples 10and 11 and Comparative Example 3.

FIG. 6 is a diagram illustrating amounts of fluorescently-labeledinsulin (fluorescence intensities in μg/cm²) in extracted solutions ofthe skin after the skin permeability test (Example 14) conducted usingtransdermally absorbable base materials (gels) and polyoxylauryl etherprepared in Example 13 and Comparative Example 4.

FIG. 7 is a diagram illustrating amounts of fluorescently-labeledinsulin (fluorescence intensities in μg/cm²) in extracted solutions ofthe skin after the skin permeability test (Example 18) conducted usingtransdermally absorbable base materials (gels) prepared in Examples 16and 17 and Comparative Example 5.

FIG. 8 depicts confocal micrographs illustrating permeability throughthe skin of a mouse ear taken using the transdermally absorbable basematerial (gel) prepared in Example 6.

FIG. 9 depicts confocal micrographs illustrating permeability throughthe skin of a mouse ear taken using the transdermally absorbable basematerial (gel) prepared in Example 16.

FIG. 10 depicts fluorescence micrographs illustrating permeabilitythrough YMP skin taken using the transdermally absorbable base material(gel) prepared in Example 16.

MODES FOR CARRYING OUT THE INVENTION

The present invention relates to a transdermally absorbable basematerial that contains a lipid peptide compound including at least oneof compounds of Formulae (1) to (3) below or pharmaceutically usablesalts thereof, a surfactant, a specific polyhydric alcohol, a fattyacid, and water, and contains, as desired, an oleaginous base material,an organic acid, and other additives.

The present invention also relates to a premix for the transdermallyabsorbable base material containing the lipid peptide compound, thesurfactant, the specific polyhydric alcohol, the fatty acid mentionedabove.

The transdermally absorbable base material of the present invention issuitable for cosmetics or pharmaceutical products, and in particular,can be suitably used as a stick-shaped transdermally absorbable basematerial (hereinafter, also called a stick-shaped base material). In thepresent invention, the stick-shaped base material refers to a bar-likebase material that retains a bar-like shape and has a strength enablingapplication to, for example, skin.

The components will be described below.

[Lipid Peptide Compound]

The lipid peptide compound used in the transdermally absorbable basematerial and the premix therefor of the present invention can be any ofcompounds (lipid peptides) of Formulae (1) to (3) below or apharmaceutically usable salt thereof (a low-molecular compounds having alipid moiety serving as a hydrophobic moiety and a peptide moietyserving as a hydrophilic moiety).

In Formula (1) above, R¹ is a C₉₋₂₃ aliphatic group, and preferably R¹is a linear aliphatic group having a carbon atom number of 11 to 23, andoptionally having 0 to 2 unsaturated bonds.

Specific examples of the lipid moiety (acyl group) constituted by R¹ andadjacent carbonyl group include lauroyl group, dodecylcarbonyl group,myristoyl group, tetradecylcarbonyl group, palmitoyl group, margaroylgroup, oleoyl group, elaidoyl group, linoleoyl group, stearoyl group,vaccenoyl group, octadecylcarbonyl group, arachidoyl group,eicosylcarbonyl group, behenoyl group, erucanoyl group, docosylcarbonylgroup, lignoceyl group, and nervonoyl group. Among them, lauroyl group,myristoyl group, palmitoyl group, margaroyl group, stearoyl group,oleoyl group, elaidoyl group, and behenoyl group are particularlypreferable.

In Formula (1) above, R² contained in the peptide moiety is a hydrogenatom or a C₁₋₄ alkyl group that optionally has a branched chain having acarbon atom number of 1 or 2.

The above-mentioned C₁₋₄ alkyl group that optionally has the branchedchain having a carbon atom number of 1 or 2 refers to the alkyl groupthat has a C₁₋₄ main chain and optionally has the branched chain havinga carbon atom number of 1 or 2, and specific examples thereof includemethyl group, ethyl group, n-propyl group, i-propyl group, n-butylgroup, i-butyl group, sec-butyl group, and tert-butyl group.

R² described above is preferably a hydrogen atom or a C₁₋₃ alkyl groupthat optionally has a branched chain having a carbon atom number of 1,and is more preferably a hydrogen atom.

The C₁₋₃ alkyl group that optionally has the branched chain having acarbon atom number of 1 refers to the alkyl group that has a C₁₋₃ mainchain and optionally has the branched chain having a carbon atom numberof 1, and specific examples thereof include methyl group, ethyl group,n-propyl group, i-propyl group, i-butyl group, and sec-butyl group.Among them, methyl group, i-propyl group, i-butyl group, and sec-butylgroup are preferable.

In Formula (1) above, R³ is a —(CH₂)_(n)—X group. In the —(CH₂)_(n)—Xgroup mentioned above, n is a number of 1 to 4, and X is amino group,guanidino group, —CONH₂ group, or a 5-membered cyclic group optionallyhaving 1 to 3 nitrogen atoms, a 6-membered cyclic group optionallyhaving 1 to 3 nitrogen atoms, or a condensed heterocyclic groupconstituted by a 5-membered cyclic group and a 6-membered cyclic groupwhich optionally have 1 to 3 nitrogen atoms.

In the —(CH₂)_(n)—X group that is R³ described above, X is preferablyamino group, guanidino group, carbamoyl group (—CONH₂ group), pyrrolegroup, imidazole group, pyrazole group, or indole group, and is morepreferably imidazole group. In the —(CH₂)_(n)—X group mentioned above, nis preferably 1 or 2, and is more preferably 1.

Accordingly, the above-described —(CH₂)_(n)—X group is preferablyaminomethyl group, 2-aminoethyl group, 3-aminopropyl group, 4-aminobutylgroup, carbamoylmethyl group, 2-carbamoyl ethyl group, 3-carbamoyl butylgroup, 2-guanidino ethyl group, 3-guanidino butyl group, pyrrole methylgroup, 4-imidazole methyl group, pyrazolemethyl group, or 3-indolemethyl group, more preferably 4-aminobutyl group, carbamoylmethyl group,2-carbamoyl ethyl group, 3-guanidino butyl group, 4-imidazole methylgroup, or 3-indole methyl group, and still more preferably 4-imidazolemethyl group.

In the compound of Formula (1) above, a particularly preferable lipidpeptide as the lipid peptide compound is one of compounds listed belowthat is formed of a lipid moiety and a peptide moiety (amino acidassembly moiety). Amino acids are abbreviated as follows: alanine (Ala),asparagine (Asn), glutamine (Gln), glycine (Gly), histidine (His),isoleucine (Be), leucine (Leu), lysine (Lys), tryptophan (Trp), andvaline (Val). The compounds are as follows: lauroyl-Gly-His,lauroyl-Gly-Gln, lauroyl-Gly-Asn, lauroyl-Gly-Trp, lauroyl-Gly-Lys,lauroyl-Ala-His, lauroyl-Ala-Gln, lauroyl-Ala-Asn, lauroyl-Ala-Trp, andlauroyl-Ala-Lys; myristoyl-Gly-His, myristoyl-Gly-Gln,myristoyl-Gly-Asn, myristoyl-Gly-Trp, myristoyl-Gly-Lys,myristoyl-Ala-His, myristoyl-Ala-Gln, myristoyl-Ala-Asn,myristoyl-Ala-Trp, and myristoyl-Ala-Lys; palmitoyl-Gly-His,palmitoyl-Gly-Gln, palmitoyl-Gly-Asn, palmitoyl-Gly-Trp,palmitoyl-Gly-Lys, palmitoyl-Ala-His, palmitoyl-Ala-Gln,palmitoyl-Ala-Asn, palmitoyl-Ala-Trp, and palmitoyl-Ala-Lys; andstearoyl-Gly-His, stearoyl-Gly-Gln, stearoyl-Gly-Asn, stearoyl-Gly-Trp,stearoyl-Gly-Lys, stearoyl-Ala-His, stearoyl-Ala-Gln, stearoyl-Ala-Asn,stearoyl-Ala-Trp, and stearoyl-Ala-Lys.

Examples of the most preferable of these compounds includelauroyl-Gly-His and lauroyl-Ala-His; myristoyl-Gly-His andmyristoyl-Ala-His; palmitoyl-Gly-His and palmitoyl-Ala-His; andstearoyl-Gly-His and stearoyl-Ala-His.

In Formula (2) above, s a C₉₋₂₃ aliphatic group, and preferable specificexamples thereof include the same groups as those defined in R¹described above.

In Formula (2) above, R⁵ to R⁷ are each independently a hydrogen atom, aC₁₋₄ alkyl group that optionally has a branched chain having a carbonatom number of 1 or 2, or —(CH₂)_(n)—X group, and at least one of R⁵ toR⁷ is preferably —(CH₂)_(n)—X group; n is a number of 1 to 4; and X isamino group, guanidino group, —CONH₂ group, or a 5-membered cyclic groupoptionally having 1 to 3 nitrogen atoms, a 6-membered cyclic groupoptionally having 1 to 3 nitrogen atoms, or a condensed heterocyclicgroup constituted by a 5-membered cyclic group and a 6-membered cyclicgroup which optionally have 1 to 3 nitrogen atoms. Preferable specificexamples of R⁵ to R⁷ include the same groups as those defined in R² andR³ described above.

In the compound of Formula (2) above, a preferable lipid peptide is oneof the following compounds that is formed of a lipid moiety and apeptide moiety (amino acid assembly moiety): myristoyl-Gly-Gly-His,myristoyl-Gly-Gly-Gln, myristoyl-Gly-Gly-Asn, myristoyl-Gly-Gly-Trp,myristoyl-Gly-Gly-Lys, myristoyl-Gly-Ala-His, myristoyl-Gly-Ala-Gln,myristoyl-Gly-Ala-Asn, myristoyl-Gly-Ala-Trp, myristoyl-Gly-Ala-Lys,myristoyl-Ala-Gly-His, myristoyl-Ala-Gly-Gln, myristoyl-Ala-Gly-Asn,myristoyl-Ala-Gly-Trp, myristoyl-Ala-Gly-Lys, myristoyl-Gly-His-Gly,myristoyl-His-Gly-Gly, palmitoyl-Gly-Gly-His, palmitoyl-Gly-Gly-Gln,palmitoyl-Gly-Gly-Asn, palmitoyl-Gly-Gly-Trp, palmitoyl-Gly-Gly-Lys,palmitoyl-Gly-Ala-His, palmitoyl-Gly-Ala-Gln, palmitoyl-Gly-Ala-Asn,palmitoyl-Gly-Ala-Trp, palmitoyl-Gly-Ala-Lys, palmitoyl-Ala-Gly-His,palmitoyl-Ala-Gly-Gln, palmitoyl-Ala-Gly-Asn, palmitoyl-Ala-Gly-Trp,palmitoyl-Ala-Gly-Lys, palmitoyl-Gly-His-Gly, palmitoyl-His-Gly-Gly,lauroyl-Gly-Gly-His, and stearoyl-Gly-Gly-His.

Examples of the most preferable of these compounds includelauroyl-Gly-Gly-His, myristoyl-Gly-Gly-His, palmitoyl-Gly-Gly-His,palmitoyl-Gly-His-Gly, palmitoyl-His-Gly-Gly, and stearoyl-Gly-Gly-His.

In Formula (3) above, R⁸ is a C₉₋₂₃ aliphatic group, and preferablespecific examples thereof include the same groups as those defined in R¹described above.

In Formula (3) above, R⁹ to R¹² are each independently a hydrogen atom,a C₁₋₄ alkyl group that optionally has a branched chain having a carbonatom number of 1 or 2, or —(CH₂)_(n)—X group, and at least one of R⁹ toR¹² is preferably —(CH₂)_(n)—X group; n is a number of 1 to 4; and X isamino group, guanidino group, —CONH₂ group, or a 5-membered cyclic groupoptionally having 1 to 3 nitrogen atoms, a 6-membered cyclic groupoptionally having 1 to 3 nitrogen atoms, or a condensed heterocyclicgroup constituted by a 5-membered cyclic group and a 6-membered cyclicgroup which optionally have 1 to 3 nitrogen atoms. Preferable specificexamples of R⁹ to R¹² include the same groups as those defined in R² andR³ described above.

Accordingly, in the compound of Formula (3) above, examples of thepreferable lipid peptide compound, in particular, the preferable lipidpeptide include lauroyl-Gly-Gly-Gly-His, myristoyl-Gly-Gly-Gly-His,palmitoyl-Gly-Gly-Gly-His, palmitoyl-Gly-Gly-His-Gly,palmitoyl-Gly-His-Gly-Gly, palmitoyl-His-Gly-Gly-Gly, andstearoyl-Gly-Gly-Gly-His.

A particularly preferable compound among these lipid peptide compoundsis a compound of Formula (1), wherein R¹ is a linear aliphatic grouphaving a carbon atom number of 15; R² is a hydrogen atom; and R³ is4-imidazole methyl group, namely, a palmitoyl-Gly-His compound.

In the present invention, the blending amount of the lipid peptidecompound with respect to the total mass of the obtained transdermallyabsorbable base material is, for example, from 0.01% to 30% by mass,preferably from 0.05% to 10% by mass, and more preferably from 0.1% to10% by mass.

In the present invention, the blending amount of the lipid peptidecompound with respect to the total mass of the obtained premix is, forexample, from 5% to 20% by mass, and preferably from 10% to 20% by mass.

The lipid peptide compound used in the present invention includes atleast one of the compounds (lipid peptides) of Formulae (1) to (3) aboveor pharmaceutically usable salts thereof. One or a combination of two ormore of these compounds can be used as a hydrogelator.

[Surfactant]

A compound having a hydrophilic moiety having a betaine structure and ahydrophobic moiety in each molecule thereof (hereinafter, also called abetaine-based compound), ethylene glycol alkyl ethers, or polyglycerinfatty acid esters can be preferably used as the surfactant used in thetransdermally absorbable base material or the premix therefor of thepresent invention.

Betaine-based compounds known as amphoteric surfactants can be used asthe betaine-based compound described above. Examples of the knownbetaine-based compounds include N-alkyl-N,N-dimethyl amino acidbetaines, such as lauryldimethyl aminoacetic acid betaine (laurylbetaine); fatty acid amide alkyl-N,N-dimethyl amino acid betaines, suchas cocamidopropyl betaine and lauramidopropyl betaine; imidazoline-typebetaines, such as sodium cocoamphoacetate and sodium lauroamphoacetate;alkyl sulfobetaines, such as lauryl hydroxy sulfobetaine and alkyldimethyl taurines; sulfuric acid-type betaines, such as alkyl dimethylamino ethanol sulfuric acid esters; and phosphoric acid-type betaines,such as alkyl dimethyl amino ethanol phosphoric acid esters.

Examples of the betaine-based compound described above includeglycerophospholipids, such as phosphatidylcholine,phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol,phosphatidylglycerol, diphosphatidylglycerol (cardiolipin), andphosphatidic acid; lysoglycerophospholipids, such aslysophosphatidylcholine (lysolecithin), lysophosphatidylethanolamine,lyzophosphatidylserine, lyzophosphatidylinositol,lyzophosphatidylglycerol, and lysophosphatidic acid;sphingophospholipids, such as sphingomyelin; and hydrogenated productsthereof. These phospholipids may be those derived from animals andplants, such as soybeans and egg yolk, or may be synthesized by chemicalor enzymatic methods.

Preferable examples of the betaine-based compound described aboveinclude lauryldimethyl aminoacetic acid betaine, lauramidopropylbetaine, lauryl hydroxy sulfobetaine, stearyl betaine,lysophosphatidylcholine (lysolecithin), lysophosphatidylethanolamine,lysophosphatidylserine, lyzophosphatidylinositol,lysophosphatidylglycerol, and lysophosphatidic acid, and more preferableexamples thereof include lysophosphatidylcholine (lysolecithin).

Examples of the above-mentioned ethylene glycol alkyl ethers includepolyoxyethylene lauryl ethers, polyoxyethylene palmitoyl ethers, andpolyoxyethylene stearyl ethers. Among them, polyoxyethylene laurylethers and polyoxyethylene stearyl ethers are preferable.

Examples of the above-mentioned polyglycerin fatty acid esters includeglycerin fatty acid partial esters, such as glyceryl stearate, glycerylisostearate, glyceryl palmitate, glyceryl myristate, glyceryl oleate,coconut oil fatty acid glyceryl, mono-cottonseed oil fatty acidglycerin, glycerin monoerucate, glycerin sesquioleate, α, α′-oleic acidpyroglutamic acid glycerin, and glycerin monostearate malic acid; andpolyglyceryl-2, -3, -4, -5, -6, -8, and -10 stearates, polyglyceryl-6and -10 distearates, polyglyceryl-2 tristearates, polyglyceryl-10decastearates, polyglyceryl-2, -3, -4, -5, -6, -8, and -10 isostearates,polyglyceryl-2 diisostearates (diglyceryl diisostearate), polyglyceryl-3and -10 diisostearates, polyglyceryl-2 triisostearates, polyglyceryl-2tetraisostearates, polyglyceryl-10 decaisostearates, polyglyceryl-2, -3,-4, -5, -6, -8, and -10 oleates, polyglyceryl-6 dioleates,polyglyceryl-2 trioleates, and polyglyceryl-10 decaoleates.

In the present invention, when the surfactant is classified based on ahydrophile-lipophile balance (HLB) value, the surfactant having an HLBvalue in the range of preferably 1.0 to 20.0, more preferably 2.0 to17.0, and still more preferably 8.0 to 17.0 can be blended. Setting theHLB value of the surfactant in the above-described range can providegood dispersibility of an emulsion that can be constituted byhydrophilic and oleophilic components when the transdermally absorbablebase material is prepared.

Specific examples of the surfactant in the above-described HLB rangeinclude sorbitan mono-fatty acid esters, such as sorbitan monolaurate[“Span 20” (registered trademark) manufactured by Wako Pure ChemicalIndustries Ltd., HLB=8.6]; and polyoxyethylene sorbitan fatty acidesters, such as polyoxyethylene (20) sorbitan monolaurates [“Tween 20”(registered trademark) manufactured by Wako Pure Chemical IndustriesLtd., HLB=16.7], polyoxyethylene (4) sorbitan monostearates (HLB=9.6),polyoxyethylene (5) sorbitan monooleates (HLB=10.0), polyoxyethylene (4)sorbitan tristearates (HLB=10.5), polyoxyethylene (4) sorbitantrioleates (HLB=11.0), and polyoxyethylene (20) sorbitan monostearates(HLB=14.9).

Although partially overlapping with the above-mentioned compounds,examples of suitably usable surfactants having a hydrophile-lipophilebalance (HLB) value of 10 to 12 include sorbitan isostearate,steareth-8, beheneth-10, laureth-5, ceteth-7, oleth-8, PEG-8 glycerylisostearate, choleth-10, PEG-10BG isostearate, PEG-30 glyceryltriisostearate, PEG-30 glyceryl trioleate, PEG-30 trimethylolpropanetriisostearate, PEG-30 hydrogenated castor oil laurate, PCA isostearatePEG-30 hydrogenated castor oil, octyldodeceth-10, PEG-12 dilaurate,sorbeth-40 tetraoleate, polyglyceryl-10 diisostearates, PEG-20 glyceryldiisostearate, PEG-8 isostearate, PEG-10 glyceryl isostearate, PEG-60hydrogenated castor oil triisostearate, PPG-2-deceth-7, oleth-10,hydrogenated dimer dilinoleth-20, coconut fatty acid sorbitan,isosteareth-10, steareth-11, PEG-30 trimethylolpropane trimyristate,PEG-40 hydrogenated castor oil isostearate, PEG-40 hydrogenated castoroil PCA isostearate, laureth-7, isoceteth-10, ceteth-10, PEG-10isostearate, PEG-10 stearate, PEG-10 oleate, PEG-10 glyceryl stearate,oleth-12, decyltetradeceth-15, choleth-15, PEG-16 dilaurate, PEG-30hydrogenated castor oil, PEG-40 glyceryl triisostearate, PEG-40 glyceryltrioleate, PEG-40 trimethylolpropane triisostearate, and PEG-40hydrogenated castor oil laurate.

In the present invention, the blending amount of the above-describedsurfactant with respect to the total mass of the obtained transdermallyabsorbable base material is, for example, from 0.1% to 20% by mass,preferably from 0.1% to 10% by mass, and more preferably from 0.1% to 5%by mass.

In the present invention, the blending amount of the above-describedsurfactant with respect to the total mass of the obtained premix is, forexample, from 1% to 20% by mass, and preferably from 2% to 10% by mass.

The surfactant used in the present invention is at least one of thesurfactants listed above. One or a combination of two or more of thesesurfactants can be used.

[1,2-Alkanediol or Glycerin]

The transdermally absorbable base material or the premix therefor of thepresent invention contains 1,2-alkanediol or glycerin.

1,2-alkanediol has a function to facilitate solubility of the lipidpeptide compound, and specific examples thereof include 1,2-pentanediol,1,2-hexanediol, 1,2-octanediol, and 1,2-decanediol. Among them,1,2-pentanediol, 1,2-hexanediol, and 1,2-octanediol are preferable, and1,2-pentanediol and 1,2-hexanediol are more preferable. The surfactantused in the present invention is at least one of the 1,2-alkanediolslisted above. One or a combination of two or more of these1,2-alkanediols can be used.

In addition to the 1,2-alkanediols listed above, glycerin is alsosuitably usable as a substance having the function to facilitate thesolubility of the lipid peptide compound in the transdermally absorbablebase material or the premix therefor of the present invention. Somecommercial products of the above-described surfactant contain glycerinas a solvent. When such commercial products are used, the glycerincontained as an ingredient in the commercial products also acts so as tofacilitate the solubility of the lipid peptide compound.

In the present invention, the blending amount of the 1,2-alkanediol orthe glycerin with respect to the total mass of the obtainedtransdermally absorbable base material is, for example, from 0.1% to 20%by mass, preferably from 0.1% to 10% by mass, and more preferably from0.1% to 5% by mass.

In the present invention, the blending amount of the 1,2-alkanediol orthe glycerin with respect to the total mass of the obtained premix is,for example, from 2% to 20% by mass, and preferably from 2% to 10% bymass.

[Fatty Acid]

The fatty acid contained in the transdermally absorbable base materialor the premix therefor of the present invention is preferably at leastone selected from the group consisting of saturated and unsaturatedC₁₀₋₂₀ fatty acids and salts thereof. Examples of the fatty acid includecapric acid, undecanoic acid, lauric acid, tridecanoic acid, myristicacid, pentadecanoic acid, palmitic acid, margaric acid, and stearicacid. Among them, capric acid, lauric acid, myristic acid, palmiticacid, and stearic acid are more preferable, and stearic acid isparticularly preferable.

The blending amount of the fatty acid used in the present invention is,for example, from 0.01% to 2.0% by mass, and preferably from 0.02% to1.0% by mass, with respect to the total mass of the obtainedtransdermally absorbable base material.

In the present invention, the blending amount of the fatty acid withrespect to the total mass of the obtained premix is, for example, from0.5% to 5% by mass, and preferably from 0.5% to 3% by mass.

The fatty acid used in the present invention is at least one selectedfrom the fatty acid group listed above. One or a combination of two ormore of these fatty acids can be used.

[Oleaginous Base]

The transdermally absorbable base material of the present invention mayfurther contain an oleaginous base material. The premix of the presentinvention can also contain the oleaginous base material.

Preferable examples of the oleaginous base used in the present inventioninclude higher (polyhydric) alcohols, such as cetanol, myristyl alcohol,oleyl alcohol, lauryl alcohol, cetostearyl alcohol, stearyl alcohol,arachyl alcohol, behenyl alcohol, jojoba alcohol, chimyl alcohol,selachyl alcohol, batyl alcohol, hexyldecanol, isostearyl alcohol,2-octyldodecanol, and dimer diol; aralkyl alcohols, such as benzylalcohol and derivatives thereof; isostearic acid, behenic acid,undecylenic acid, 12-hydroxystearic acid, palmitoleic acid, oleic acid,linoleic acid, linolenic acid, erucic acid, docosahexaenoic acid,eicosapentaenoic acid, isohexadecanoic acid, anteiso-heneicosanoic acid,long-chain branched fatty acids, dimeric acid, hydrogenated dimericacid, and the like; hydrocarbons, such as liquid paraffin (mineral oil),heavy liquid isoparaffin, light liquid isoparaffin, an α-olefinoligomer, polyisobutenes, hydrogenated polyisobutenes, polybutenes,squalane, squalane derived from olive, squalene, vaseline, and solidparaffin; waxes, such as candelilla wax, carnauba wax, rice wax, Japanwax, beeswax, montan wax, ozokerite, ceresin, paraffin wax,microcrystalline wax, petrolatum, Fischer-Tropsch wax, polyethylene wax,and ethylene-propylene copolymers; vegetable oils and fats, such ascoconut oil, palm oil, palm kernel oil, safflower oil, olive oil, castoroil, avocado oil, sesame oil, tea seed oil, evening primrose oil, wheatgerm oil, macadamia nut oil, hazelnut oil, candlenut oil, rose hip oil,meadowfoam oil, persic oil, tea tree oil, peppermint oil, corn oil,rapeseed oil, sunflower oil, wheat germ oil, linseed oil, cotton seedoil, soybean oil, peanut oil, rice bran oil, cacao butter, shea butter,hydrogenated coconut oil, hydrogenated castor oil, jojoba oil, andhydrogenated jojoba oil; animal oils and fats, such as beef tallow, milkfat, horse fat, egg yolk oil, mink oil, and turtle oil; animal waxes,such as spermaceti wax, lanolin, and orange roughy oil; lanolins, suchas liquid lanolin, reduced lanolin, adsorption-purified lanolin, lanolinacetate, acetylated lanolin, hydroxylanolin, polyoxyethylene lanolins,lanolin fatty acid, hard lanolin fatty acid, lanolin alcohol, acetylatedlanolin alcohol, and acetic acid (cetyl/lanolyl) esters; sterols, suchas cholesterol, dihydrocholesterol, lanosterol, dihydrolanosterol,phytosterol, and cholic acid; sapogenins; saponins; sterol esters, suchas cholesteryl acetate, cholesteryl nonanoate, cholesteryl stearate,cholesteryl isostearate, cholesteryl oleate,di(cholesteryl/behenyl/octyldodecyl) N-lauroyl-L-glutamate,di(cholesteryl/octyldodecyl) N-lauroyl-L-glutamate,di(phytosteryl/behenyl/octyldodecyl) N-lauroyl-L-glutamate,di(phytosteryl/octyldodecyl) N-lauroyl-L-glutamate, acyl sarcosine alkylesters such as isopropyl N-lauroylsarcosinate, cholesteryl12-hydroxystearate, macadamia nut oil fatty acid cholesteryl, macadamianut oil fatty acid phytosteryl, phytosteryl isostearate, soft lanolinfatty acid cholesteryl, hard lanolin fatty acid cholesteryl, long-chainbranched fatty acid cholesteryl, and long-chain α-hydroxy fatty acidcholesteryl; lipid complexes, such as phospholipid-cholesterol complexand phospholipid-phytosterol complex; monoalcohol carboxylic acidesters, such as octyldodecyl myristate, hexyldecyl myristate, tetradecylmyristate, octyldodecyl isostearate, cetyl palmitate, octyldodecylpalmitate, cetyl octanoate, hexyldecyl octanoate, isotridecylisononanoate, isononyl isononanoate, octyl isononanoate, isotridecylisononanoate, isodecyl neopentanoate, isotridecyl neopentanoate,isostearyl neopentanoate, octyldodecyl neodecanoate, oleyl oleate,octyldodecyl oleate, octyldodecyl ricinoleate, lanolin fatty acidoctyldodecyl, hexyldecyl dimethyloctanoate, octyldodecyl erucate,hydrogenated castor oil isostearate, ethyl oleate, avocado oil fattyacid ethyl, isopropyl myristate, isopropyl palmitate, octyl palmitate,isopropyl isostearate, lanolin fatty acid isopropyl, diethyl sebacate,diisopropyl sebacate, dioctyl sebacate, diisopropyl adipate,dibutyloctyl sebacate, diisobutyl adipate, dioctyl succinate, andtriethyl citrate; oxy acid esters, such as cetyl lactate, diisostearylmalate, and hydrogenated castor oil monoisostearate; polyhydric alcoholfatty acid esters, such as glyceryl trioctanoate [glyceryltri(2-ethylhexanoate)], glyceryl trioleate, glyceryl triisostearate,glyceryl diisostearate, glyceryl tri(caprylate/caprinate), glyceryltri(caprylate/caprinate/myristate/stearate), hydrogenated rosintriglyceride (hydrogenated ester gum), rosin triglyceride (ester gum),glyceryl behenate/eicosanedienoate, trimethylolpropane trioctanoate,trimethylolpropane triisostearate, neopentyl glycol dioctanoate,neopentyl glycol dicaprinate, 2-butyl-2-ethyl-1,3-propanedioldioctanoate, propylene glycol dioleate, pentaerythrityl tetraoctanoate,hydrogenated rosin pentaerythrityl, ditrimethylolpropanetriethylhexanoate, ditrimethylolpropane (isostearate/sebacate),pentaerythrityl triethylhexanoate, dipentaerythrityl(hydroxystearate/stearate/rosinate), diglyceryl diisostearate,polyglyceryl tetraisostearates, polyglyceryl-10 nonaisostearates,polyglyceryl-8 deca(erucate/isostearate/ricinoleate), diglyceryloligoesters (hexyldecanoate/sebacate), glycol distearate (ethyleneglycol distearate), 3-methyl-1,5-pentanediol dineopentanoate, and2,4-diethyl-1,5-pentanediol dineopentanoate; derivatives of dimer acidsand dimer diols, such as diisopropyl dimer dilinoleate, diisostearyldimer dilinoleate, di(isostearyl/phytosteryl) dimer dilinoleate,(phytosteryl/behenyl) dimer dilinoleate,(phytosteryl/isostearyl/cetyl/stearyl/behenyl) dimer dilinoleate, dimerdilinoleyl dimer dilinoleate, dimer dilinoleyl diisostearate, dimerdilinoleyl hydrogenated rosin condensate, hydrogenated castor oil dimerdilinoleate, and hydroxyalkyl dimer dilinoleyl ethers; fatty acidalkanolamides, such as coconut oil fatty acid monoethanolamide (cocamideMEA), coconut oil fatty acid diethanolamide (cocamide DEA), lauric acidmonoethanolamide (lauramide MEA), lauric acid diethanolamide (lauramideDEA), lauric acid monoisopropanolamide (lauramide MIPA), palmitic acidmonoethanolamide (palmitamide MEA), palmitic acid diethanolamide(palmitamide DEA), and coconut oil fatty acid methylethanolamide(cocamide methyl MEA); silicones, such as dimethicone(dimethylpolysiloxane), highly polymerized dimethicones (highlypolymerized dimethyl polysiloxanes), cyclomethicone (cyclicdimethylsiloxane, decamethylcyclopentasiloxane, or simplycyclopentasiloxane), phenyl trimethicone, diphenyl dimethicone, phenyldimethicone, stearoxypropyldimethylamine, (aminoethylaminopropylmethicone/dimethicone) copolymers, dimethiconol, dimethiconolcrosspolymers, silicone resins, silicone rubber, amino-modifiedsilicones such as aminopropyl dimethicone and amodimethicone,cation-modified silicone, polyether-modified silicones such asdimethicone copolyols, polyglycerin-modified silicones, sugar-modifiedsilicones, carboxylic acid-modified silicones, phosphoric acid-modifiedsilicones, sulfuric acid-modified silicones, alkyl-modified silicones,fatty acid-modified silicones, alkyl ether-modified silicones, aminoacid-modified silicones, peptide-modified silicones, fluorine-modifiedsilicones, cation-modified and polyether-modified silicones,amino-modified and polyether-modified silicones, alkyl-modified andpolyether-modified silicones, and polysiloxane-oxyalkylene copolymers;and fluorine-based oil solutions such as perfluorodecane,perfluorooctane, and perfluoropolyethers.

In the present invention, the blending amount of the fatty acid withrespect to the total mass of the obtained transdermally absorbable basematerial is, for example, from 1% to 50% by mass, preferably from 5% to50% by mass, and more preferably from 10% to 50% by mass.

In the present invention, if the premix includes the oleaginous basematerial, the blending amount thereof is, for example, from 1% to 50% bymass, and preferably from 1% to 30% by mass, with respect to the totalmass of the premix.

The above-described oleaginous base used in the present invention is atleast one of the oleaginous bases listed above. One or a combination oftwo or more of these oleaginous bases can be used.

[Organic Acid]

The transdermally absorbable base material of the present invention mayfurther contain an organic acid. The premix of the present invention canalso contain the organic acid.

Examples of the organic acid include oxalic acid, ascorbic acid, citricacid, lactic acid, glycolic acid, succinic acid, acetic acid, malicacid, tartaric acid, and fumaric acid. Preferable examples thereofinclude ascorbic acid, citric acid, and lactic acid, and particularlypreferable examples thereof include oxalic acid, ascorbic acid, andcitric acid.

In the present invention, the blending amount of the organic acid withrespect to the total mass of the obtained transdermally absorbable basematerial is, for example, from 0.5% to 50% by mass, and preferably from0.5% to 30% by mass.

In the present invention, if the premix includes the organic acid, theblending amount thereof is, for example, from 1% to 20% by mass, andpreferably from 1% to 10% by mass, with respect to the total mass of thepremix.

[Other Additives]

The transdermally absorbable base material of the present invention canbe blended, as needed, with additives generally usable as additives forcosmetics or additives for quasi-drugs. Examples of added ingredients,such as biologically active substances and functional substances,blended in the transdermally absorbable base material (solid basematerial for skin external application) of cosmetics or quasi-drugsinclude humectants, touch improvers, surfactants, transdermal absorptionenhancers, polymers, thickeners/gelators, solvents/propellants,antioxidants, reductants, oxidants, preservatives, antimicrobe agents,bactericides, chelating agents, pH adjusters, acids, alkalis, powder,inorganic salts, ultraviolet absorbers, whitening agents, vitamins andderivatives thereof, hair growth drugs, blood circulation accelerators,stimulants, hormones, anti-wrinkle agents, anti-aging agents, tighteningagents, cooling agents, warming agents, wound healing accelerators,irritation reducing agents, analgesics, cell activators,plant/animal/microbial extracts, antipruritic agents, corneumreleasing/dissolving agents, antiperspirants, refrigerants, astringentagents, enzymes, nucleic acids, fragrances, dyestuffs, colorants, dyes,pigments, antiphlogistic agents, antiinflammatory agents, antiasthmaticagents, anti-chronic obstructive pulmonary disease agents, antiallergicagents, immunomodulators, anti-infective agents, and antifungal agents.

Preferable examples of the humectant and touch improver include polyols,such as glycerin, 1,3-butylene glycol (1,3-butanediol), propyleneglycol, 3-methyl-1,3-butanediol, 1,3-propanediol,2-methyl-1,3-propanediol, trimethylolpropane, pentaerythritol, hexyleneglycol, diglycerin, polyglycerins, diethylene glycol, polyethyleneglycols, dipropylene glycol, polypropylene glycols, and ethyleneglycol-propylene glycol copolymers, and polymers of these polyols;glycol alkyl ethers, such as diethylene glycol monoethyl ether (ethoxydiglycol), ethylene glycol monoethyl ether, ethylene glycol monobutylether, and diethylene glycol dibutyl ether; water soluble esters, suchas polyglyceryl-10 (eicosanedienoate/tetradecanedienoate) andpolyglyceryl-10 tetradecanedienoates; sugar alcohols, such as sorbitol,xylitol, erythritol, mannitol, and maltitol; saccharides, such asglucose, fructose, galactose, mannose, threose, xylose, arabinose,fucose, ribose, deoxyribose, maltose, trehalose, lactose, raffinose,gluconic acid, glucuronic acid, cyclodextrins (α-, β-, andβ-cyclodextrins, and modified cyclodextrins such as maltosylatedcyclodextrin and hydroxyalkylated cyclodextrins), β-glucan, chitin,chitosan, heparin and derivatives thereof, pectin, arabinogalactan,dextrin, dextran, glycogen, ethyl glucoside, and polymers or copolymersof glucosylmethyl methacrylate, and derivatives of these saccharides;hyaluronic acid and sodium hyaluronate; sodium chondroitin sulfate;mucoitin sulfate, charonin sulfate, keratosulfate, and dermatan sulfate;Tremella fuciformis extracts and Tremella fuciformis polysaccharides;fucoidan; tuberosa polysaccharides or natural polysaccharides; organicacids, such as citric acid, tartaric acid, and lactic acid, and saltsthereof; urea and derivatives thereof; 2-pyrrolidone-5-carboxylic acidand salts thereof, such as a sodium salt; amino acids, such as betaine(trimethylglycine), proline, hydroxyproline, arginine, lysine, serine,glycine, alanine, phenylalanine, tyrosine, β-alanine, threonine,glutamic acid, glutamine, asparagine, aspartic acid, cysteine,methionine, leucine, isoleucine, valine, tryptophan, histidine, andtaurine, and salts of these amino acids; protein peptides, such ascollagen, fish-derived collagen, atelocollagen, gelatin, elastin,collagen-decomposed peptide, hydrolyzed collagen, hydroxypropylammoniumchloride-hydrolyzed collagen, elastin-decomposed peptide,keratin-decomposed peptide, hydrolyzed keratin, conchiolin-decomposedpeptide, hydrolyzed conchiolin, silk protein-decomposed peptide,hydrolyzed silk, lauroyl-hydrolyzed silk sodium, soybeanprotein-decomposed peptide, wheat-protein decomposed peptide, hydrolyzedwheat protein, casein-decomposed peptide, and acylated peptide, andderivatives of these protein peptides; acylated peptides, such aspalmitoyl oligopeptide, palmitoyl pentapeptide, and palmitoyltetrapeptide; silylated peptides; culture solution of lactic acidbacteria, yeast extract liquid, eggshell membrane protein, mucin frombovine submaxillary gland, hypotaurine, sesame lignan glycoside,glutathione, albumin, and milk serum; choline chloride andphosphorylcholine; animal/plant extracted components, such as placentaextract liquid, elastin, collagen, aloe extract, hamamelis water, loofahwater, chamomilla extract, licorice extract, comfrey extract, silkextract, chestnut rose extract, yarrow extract, eucalyptus extract, andmelilot extract; and ceramides, such as natural ceramides (types 1, 2,3, 4, 5, and 6), hydroxyceramide, pseudo-ceramide, sphingoglycolipid,and extracts containing ceramide or ceramide saccharide.

Preferable examples of the surfactant include anionic surfactants,nonionic surfactants, cationic surfactants, amphoteric surfactants, andpolymeric surfactants. Preferable examples of the surfactant are asfollows. Preferable examples of the anionic surfactants include salts offatty acids, such as potassium laurate and potassium myristate; alkylsulfates, such as sodium lauryl sulfate, triethanolamine lauryl sulfate,and ammonium lauryl sulfate; polyoxyethylene alkyl sulfates, such assodium laureth sulfate and triethanolamine laureth sulfate; salts ofacyl-N-methylamino acids, such as sodium cocoyl methyl taurate,potassium cocoyl methyl taurate, sodium lauroyl methyl taurate, sodiummyristoyl methyl taurate, sodium lauroyl methyl alaninate, sodiumlauroyl sarcosinate, triethanolamine lauroyl sarcosinate, and sodiummethylalanine lauroyl glutamate; salts of acylamino acids, such assodium cocoyl glutamate, triethanolamine cocoyl glutamate, sodiumlauroyl glutamate, sodium myristoyl glutamate, sodium stearoylglutamate, ditriethanolamine palmitoyl aspartate, and triethanolaminecocoyl alaninate; polyoxyethylene alkyl ether acetates, such as sodiumlaureth acetate; succinic acid ester salts, such as sodium lauroylmonoethanolamide succinate; fatty acid alkanolamide ether carboxylates;acyl lactates; polyoxyethylene aliphatic amine sulfates; fatty acidalkanolamide sulfates; fatty acid glyceride sulfates, such as glycerinhydrogenated coconut oil fatty acid sulfate sodium salt; alkylbenzenepolyoxyethylene sulfates; olefin sulfonates, such as sodium α-olefinsulfonate; alkyl sulfosuccinates, such as disodium lauryl sulfosuccinateand sodium dioctylsulfosuccinate; alkyl ether sulfosuccinates, such asdisodium laureth sulfosuccinate, sodium monolauroyl monoethanolamidepolyoxyethylene sulfosuccinates, and sodium lauryl polypropylene glycolsulfosuccinates; alkylbenzene sulfonates, such as sodiumtetradecylbenzene sulfonate and triethanolamine tetradecylbenzenesulfonate; alkyl naphthalene sulfonates; alkane sulfonates; methyl estersalts of α-sulfofatty acids; acylisethionic acid salts; alkyl glycidylether sulfonates; alkyl sulfo acetates; alkyl ether phosphates, such assodium laureth phosphate, sodium dilaureth phosphate, sodium trilaurethphosphate, and sodium monooleth phosphate; alkyl phosphates, such aspotassium lauryl phosphate; sodium caseinate; alkyl aryl etherphosphates; fatty acid amide ether phosphates; phospholipids, such asphosphatidylglycerol, phosphatidylinositol, and phosphatidic acid; andsilicone-based anionic surfactants, such as carboxylic acid-modifiedsilicones, phosphoric acid-modified silicones, and sulfuricacid-modified silicones. Preferable examples of the nonionic surfactantsinclude polyoxyethylene alkyl ethers having various numbers of addedpolyoxyethylenes, such as laureths (polyoxyethylene lauryl ethers),ceteths (polyoxyethylene cetyl ethers), steareths (polyoxyethylenestearyl ethers), beheneths (polyoxyethylene behenyl ethers),isosteareths (polyoxyethylene isostearyl ethers), and octyldodeceths(polyoxyethylene octyldodecyl ethers); polyoxyethylene alkyl phenylethers; derivatives of castor oil and hydrogenated castor oil, such aspolyoxyethylene hydrogenated castor oils, polyoxyethylene castor oils,polyoxyethylene hydrogenated castor oil monoisostearates,polyoxyethylene hydrogenated castor oil triisostearates, polyoxyethylenehydrogenated castor oil monopyroglutamate-monoisostearate-diesters, andpolyoxyethylene hydrogenated castor oil maleates; polyoxyethylenephytosterols; polyoxyethylene cholesterols; polyoxyethylenecholestanols; polyoxyethylene lanolins; polyoxyethylene reducedlanolins; polyoxyethylene-polyoxypropylene alkyl ethers, such aspolyoxyethylene-polyoxypropylene cetyl ethers,polyoxyethylene-polyoxypropylene 2-decyltetradecyl ethers,polyoxyethylene-polyoxypropylene monobutyl ethers,polyoxyethylene-polyoxypropylene hydrogenated lanolins, andpolyoxyethylene-polyoxypropylene glycerin ethers;polyoxyethylene-polyoxypropylene glycols; (poly)glycerinpolyoxypropylene glycols, such as PPG-9 diglyceryl; glycerin fatty acidpartial esters, such as glyceryl stearate, glyceryl isostearate,glyceryl palmitate, glyceryl myristate, glyceryl oleate, coconut oilfatty acid glyceryl, mono-cottonseed oil fatty acid glycerin, glycerinmonoerucate, glycerin sesquioleate, α, α′-oleic acid pyroglutamic acidglycerin, and glycerin monostearate malic acid; polyglycerin fatty acidesters, such as polyglyceryl-2, -3, -4, -5, -6, -8, and -10 stearates,polyglyceryl-6 and -10 distearates, polyglyceryl-2 tristearate,polyglyceryl-10 decastearates, polyglyceryl-2, -3, -4, -5, -6, -8, and-10 isostearates, polyglyceryl-2 diisostearates (diglyceryldiisostearate), polyglyceryl-3 and -10 diisostearates, polyglyceryl-2triisostearates, polyglyceryl-2 tetraisostearates, polyglyceryl-10decaisostearates, polyglyceryl-2, -3, -4, -5, -6, -8, and -10 oleates,polyglyceryl-6 dioleates, polyglyceryl-2 trioleates, and polyglyceryl-10decaoleates; ethylene glycol mono-fatty acid esters, such as ethyleneglycol monostearate; propylene glycol mono-fatty acid esters, such aspropylene glycol monostearate; pentaerythritol partial fatty acid ester;sorbitol partial fatty acid ester; maltitol partial fatty acid ester;maltitol ether; sorbitan fatty acid esters, such as sorbitan monooleate,sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate,sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate,diglycerol sorbitan penta-2-ethylhexylate, and diglycerol sorbitantetra-2-ethylhexylate; sugar derivative partial esters, such as sucrosefatty acid ester, methylglucoside fatty acid ester, and trehaloseundecylenate; alkyl glucosides, such as caprylyl glucoside;alkylpolyglucosides; lanolin alcohol; reduced lanolin; polyoxyethylenefatty acid mono- and di-esters, such as polyoxyethylene distearates,polythylene glycol diisostearates, polyoxyethylene monooleates, andpolyoxyethylene dioleates; polyoxyethylene propylene glycol fatty acidesters; polyoxyethylene glycerin fatty acid esters, such aspolyoxyethylene monooleates such as polyoxyethylene glycerinmonostearates, polyoxyethylene glycerin monoisostearates, andpolyoxyethylene glycerin triisostearates; polyoxyethylene sorbitan fattyacid esters, such as polyoxyethylene sorbitan monolaurates,polyoxyethylene sorbitan monooleates, polyoxyethylene sorbitanmonostearates, polyoxyethylene sorbitan monoolates, and polyoxyethylenesorbitan tetraoleates; polyoxyethylene sorbitol fatty acid esters, suchas polyoxyethylene sorbitol monolaurates, polyoxyethylene sorbitolmonooleates, polyoxyethylene sorbitol pentaoleates, and polyoxyethylenesorbitol monostearates; polyoxyethylene methylglucoside fatty acidesters; polyoxyethylene alkyl ether fatty acid esters; polyoxyethyleneanimal and plant oils and fats, such as polyoxyethylene sorbitolbeeswaxes; alkyl glyceryl ethers, such as isostearyl glyceryl ether,chimyl alcohol, selachyl alcohol, and batyl alcohol; polyhydric alcoholalkyl ethers; polyoxyethylene alkylamines;tetrapolyoxyethylene/tetrapolyoxypropylene-ethylenediamine condensates;natural surfactants, such as saponin and sophorolipid; polyoxyethylenefatty acid amides; fatty acid alkanolamides, such as coconut oil fattyacid monoethanolamide (cocamide MEA), coconut oil fatty aciddiethanolamide (cocamide DEA), lauric acid monoethanolamide (lauramideMEA), lauric acid diethanolamide (lauramide DEA), lauric acidmonoisopropanolamide (lauramide MIPA), palmitic acid monoethanolamide(palmitamide MEA), palmitic acid diethanolamide (palmitamide DEA), andcoconut oil fatty acid methylethanolamide (cocamide methyl MEA);alkyldimethylamine oxides, such as lauramine oxide, cocamine oxide,stearamine oxide, and behenamine oxide; alkylethoxydimethylamine oxides;polyoxyethylene alkyl mercaptans; and silicone-based nonionicsurfactants, such as polyether-modified silicones such as dimethiconecopolyols, polysiloxane-oxyalkylene copolymers, polyglycerin-modifiedsilicones, and sugar-modified silicones. Preferable examples of thecationic surfactants include alkyltrimethylammonium chlorides, such asbehentrimonium chloride, steartrimonium chloride, cetrimonium chloride,and lauryltrimonium chloride; alkyltrimethylammonium bromides, such assteartrimonium bromide; dialkyldimethylammonium chlorides, such asdistearyldimonium chloride and dicocodimonium chloride; fatty acid amidoamines, such as stearamidopropyl dimethylamine and stearamidoethyldiethylamine, and salts thereof; alkyletheramines, such asstearoxypropyl dimethylamine, and salts or quaternary salts thereof;fatty acid amide-type quaternary ammonium salts, such as long-chainbranched fatty acid (12 to 31) aminopropylethyldimethylammonium ethylsulfate and lanolin fatty acid aminopropylethyldimethylammonium ethylsulfate; polyoxyethylene alkylamines and salts or quaternary saltsthereof; alkylamine salts; fatty acid amide guanidium salts; alkyl etherammonium salts; alkyl trialkylene glycol ammonium salts; benzalkoniumsalts; benzethonium salts; pyridinium salts, such as cetylpyridiniumchloride; imidazolinium salts; alkyl isoquinolinium salts; dialkylmorpholinium salts; polyamine fatty acid derivatives; and silicone-basedcationic surfactants, such as amino-modified silicones such asaminopropyl dimethicone and amodimethicone, cation-modified silicones,cation-modified and polyether-modified silicones, and amino-modified andpolyether-modified silicones. Preferable examples of the amphotericsurfactants include N-alkyl-N,N-dimethyl amino acid betaines, such aslauryl betaine (lauryldimethyl aminoacetic acid betaine); fatty acidamide alkyl-N,N-dimethyl amino acid betaines, such as cocamidopropylbetaine and lauramidopropyl betaine; imidazoline-type betaines, such assodium cocoamphoacetate and sodium lauroamphoacetate; alkylsulfobetaines, such as alkyl dimethyl taurines; sulfuric acid-type betaines,such as alkyl dimethyl amino ethanol sulfuric acid esters; phosphoricacid-type betaines, such as alkyl dimethyl amino ethanol phosphoric acidesters; phospholipids, such as phosphatidylcholine,phosphatidylethanolamine, phosphatidylserine, sphingophospholipids, suchas sphingomyelin, lysolecithin, hydrogenated soybean phospholipid,partially hydrogenated soybean phospholipid, hydrogenated egg yolkphospholipid, partially hydrogenated egg yolk phospholipid, and lecithinhydroxide; and silicone-based amphoteric surfactants. Preferableexamples of the polymeric surfactants include polyvinyl alcohols, sodiumalginate, starch derivatives, tragacanth gum, copolymers of alkylacrylates or alkyl methacrylates, and various silicone-basedsurfactants.

Examples of the transdermal absorption enhancers include caprylic acid,capric acid, caproic acid, lauric acid, myristic acid, palmitic acid,stearic acid, isostearic acid, oleic acid, linoleic acid, linolenicacid, isopropyl myristate, isopropyl palmitate, lauryl alcohol, myristylalcohol, oleyl alcohol, isostearyl alcohol, cetyl alcohol, lauric aciddiethanolamide, methyl salicylate, ethylene glycol salicylate, cinnamicacid, methyl cinnamate, cresol, cetyl lactate, lauryl lactate, ethylacetate, propyl acetate, geraniol, thymol, eugenol, terpineol,L-menthol, borneol, d-limonene, isoeugenol, isoborneol, nerol,dl-camphor, glycerin monocaprylate, glycerin monocaprate, glycerinmonolaurate, glycerin monooleate, sorbitan monolaurate, sucrosemonolaurate, polysorbate 20, propylene glycol monolaurate, propyleneglycol monocaprylate, propylene glycol dicaprylate, polyethylene glycolmonolaurates, polyethylene glycol monostearates, polyoxyethylene oleylethers, polyoxyethylene lauryl ethers, jojoba oil, squalane, olive oil,silicone oil, liquid paraffin, n-methyl-2-pyrrolidone, dl-camphor, andpeppermint oil.

Preferable examples of the polymers, the thickeners, and the gelatorsinclude guar gum; locust bean gum; quince seed; carrageenan; galactan;gum arabic; tara gum; tamarind; furcellaran; karaya gum; sunsethibiscus; cara gum; tragacanth gum; pectin; pectic acid and saltsthereof, such as a sodium salt; alginic acid and salts thereof, such asa sodium salt; mannan; starches of, for example, rice, corn, potato, andwheat; xanthan gum; dextran; succinoglucan; curdlan; hyaluronic acid andsalts thereof; xanthan gum; pullulan, gellan gum; chitin; chitosan;agar; brown alga extract; chondroitin sulfate; casein; collagen;gelatin; albumin; celluloses and derivatives thereof, such as methylcellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose andsalts such as a sodium salt thereof, methylhydroxypropyl cellulose,sodium cellulose sulfate, dialkyldimethyl ammonium sulfate celluloses,crystalline cellulose, and powdered cellulose; starch polymers, such assoluble starch, carboxymethyl starch, methylhydroxypropyl starch, andmethyl starch; starch derivatives, such as starch hydroxypropyltrimoniumchloride, and aluminum corn starch octenylsuccinate; alginic acidderivatives, such as sodium alginate and propylene glycol alginateester; polyvinylpyrrolidones (PVP); polyvinylalcohols (PVA);vinylpyrrolidone-vinylalcohol copolymers; polyvinyl methyl ethers;polyethylene glycols; polypropylene glycols;polyoxyethylene-polyoxypropylene copolymers; amphoteric methacrylateester copolymers, such as (methacryloyloxyethyl carboxybetaine/alkylmethacrylate) copolymers and (acrylate/stearyl acrylate/ethylamine oxidemethacrylate) copolymers; (dimethicone/vinyldimethicone) crosspolymers;(alkyl acrylate/diacetone acrylamide) copolymers and AMP-(alkylacrylate/diacetone acrylamide) copolymers; polyvinyl acetate partiallysaponified products; maleic acid copolymers;vinylpyrrolidone-dialkylaminoalkyl methacrylate copolymers; acrylicresin alkanolamines; polyesters and water-dispersible polyesters;polyacrylamides; copolymers of polyacrylate esters, such as ethylpolyacrylates; carboxyvinyl polymers; polyacrylic acids and saltsthereof, such as a sodium salt; copolymers of acrylic acid andmethacrylate esters; copolymers of alkyl acrylates and alkylmethacrylates; cationized celluloses, such as polyquaternium-10;diallyldimethylammonium chloride-acrylamide copolymers, such aspolyquaternium-7; acrylic acid-diallyldimethylammonium chloridecopolymers, such as polyquaternium-22; acrylicacid-diallyldimethylammonium chloride-acrylamide copolymers, such aspolyquaternium-39; acrylic acid-cationized methacrylate estercopolymers; acrylic acid-cationized methacrylamide copolymers;copolymers of acrylic acid-methylacrylate-methacrylamidepropyltrimethylammonium chloride, such aspolyquaternium-47; methacrylate chloride choline ester polymers;cationized polysaccharides, such as cationized oligosaccharides,cationized dextran, and guar hydroxypropyltrimonium chloride;polyethyleneimines; cationic polymers; copolymers of polymers of2-methacryloyloxyethyl phosphorylcholine and butyl methacrylatecopolymers, such as polyquaternium-51; polymer emulsions, such asacrylic resin emulsions, ethyl polyacrylate emulsions, polyacrylalkylester emulsions, polyvinyl acetate resin emulsions, natural rubberlatex, and synthetic latex; nitrocelluloses; polyurethanes and variouscopolymers thereof; various silicones; various silicone-basedcopolymers, such as acryl-silicone graft copolymers; variousfluorine-based polymers; 12-hydroxystearic acid and salts thereof;dextrin fatty acid esters, such as dextrin palmitate and dextrinmyristate; silicic anhydride; fumed silica (ultrafine particulatesilicic anhydride); magnesium aluminum silicate; sodium magnesiumsilicate; metal soaps; dialkylphosphoric acid metal salts; bentonite;hectorite; organic modified clay minerals; saccharose fatty acid esters;and fructo-oligosaccharide fatty acid esters. Preferable examples amongthe above-listed examples include celluloses and derivatives thereof,alginic acid and salts thereof, polyvinylalcohols, hyaluronic acid andsalts thereof, and collagen.

Preferable examples of the solvents and the propellants include loweralcohols, such as ethanol, 2-propanol (isopropyl alcohol), butanol, andisobutyl alcohol; glycols, such as propylene glycol, 1,3-butyleneglycol, diethylene glycol, dipropylene glycol, and isopentyl diol;glycol ethers, such as diethylene glycol monoethyl ether (ethoxydiglycol), ethylene glycol monoethyl ether, ethylene glycol monobutylether, triethylene glycol monoethyl ether, diethylene glycol diethylether, diethylene glycol dibutyl ether, propylene glycol monoethylether, and dipropylene glycol monoethyl ether; glycol ether esters, suchas ethylene glycol monoethyl ether acetate, diethylene glycol monoethylether acetate, and propylene glycol monoethyl ether acetate; glycolesters, such as diethoxyethyl succinate and ethylene glycol disuccinate;benzyl alcohol; benzyloxyethanol; propylene carbonate; dialkylcarbonates; acetone; ethyl acetate; N-methylpyrrolidone; toluene;fluorocarbon and next generation freon; LPG, dimethyl ether, and carbondioxide.

Preferable examples of the antioxidants include tocopherol derivatives,such as tocopherol (vitamin E) and tocopherol acetate; BHT and BHA;gallic acid derivatives, such as propyl gallate; vitamin C (ascorbicacid) and/or derivatives thereof; erythorbic acid and derivativesthereof; sulfites, such as sodium sulfite; hydrogen sulfites, such assodium hydrogensulfite; thiosulfates, such as sodium thiosulfate;metabisulfites; thiotaurine; hypotaurine; thioglycerol; thiourea;thioglycolic acid; and cysteine hydrochloride.

Preferable examples of the reducing agents include thioglycolic acid,cysteine, and cysteamine.

Preferable examples of the oxidants include a hydrogen peroxidesolution, ammonium persulfate, sodium bromate, and percarbonic acid.

Preferable examples of the preservatives, the antimicrobe agents, andthe bactericides include hydroxybenzoic acid and salts or estersthereof, such as methylparaben, ethylparaben, propylparaben, andbutylparaben; salicylic acid; sodium benzoate; phenoxy ethanol;isothiazolinone derivatives, such as methyl-chloro-isothiazolinone andmethyl-isothiazolinone; imidazolinium urea; dehydroacetic acid and saltsthereof; phenols; halogenated bisphenols, such as triclosan; acidamides; quaternary ammonium salts; trichlorocarbanilide; zincpyrithione; benzalkonium chloride; benzethonium chloride; sorbic acid;chlorhexidine; chlorhexidine gluconate; halocarban; hexachlorophene;hinokitiol; other phenols, such as phenol, isopropylphenol, cresol,thymol, parachlorophenol, phenylphenol, and phenylphenol sodium;phenylethyl alcohol; photosensitive elements; antibacterial zeolite; andsilver ion.

Preferable examples of the chelating agents include edetates(ethylenediaminetetraacetates), such as EDTA, EDTA2Na, EDTA3Na, andEDTA4Na; hydroxyethylethylenediaminetriacetates, such as HEDTA3Na;pentetate (diethylenetriaminepentaacetate); phytic acid; phosphonicacids, such as etidronic acid and salts thereof, such as a sodium salt;polyamino acids, such as polyaspartic acids and polyglutamic acids;sodium polyphosphates; sodium metaphosphate; phosphoric acid; sodiumcitrate; citric acid; alanine; dihydroxyethylglycine; gluconic acid;ascorbic acid; succinic acid; and tartaric acid.

Preferable examples of the pH adjusters, the acids, and the alkalisinclude citric acid, sodium citrate, lactic acid, sodium lactate,potassium lactate, glycolic acid, succinic acid, acetic acid, sodiumacetate, malic acid, tartaric acid, fumaric acid, phosphoric acid,hydrochloric acid, sulfuric acid, monoethanolamine, diethanolamine,triethanolamine, isopropanolamine, triisopropanolamine,2-amino-2-methyl-1,3-propandiol,2-amino-2-hydroxymethyl-1,3-propanediol, arginine, sodium hydroxide,potassium hydroxide, ammonia water, guanidine carbonate, and ammoniumcarbonate.

Preferable examples of the powder include inorganic powder havingvarious sizes and shapes, such as mica, talc, kaolin, sericite,montmorillonite, kaolinite, isinglass, muscovite, phlogopite, syntheticmica, lepidolite, biotite, vermiculite, magnesium carbonate, calciumcarbonate, aluminum silicate, barium silicate, calcium silicate,magnesium silicate, strontium silicate, metal salts of tungstic acid,magnesium, zeolite, barium sulfate, baked calcium sulfate, calciumphosphate, fluorapatite, hydroxyapatite, ceramic powder, bentonite,smectite, clay, mud, metal soap (such as zinc myristate, calciumpalmitate, aluminum stearate), calcium carbonate, red iron oxide, yellowiron oxide, black iron oxide, ultramarine blue, Prussian blue, carbonblack, titanium oxide, fine particles and ultrafine particles oftitanium oxide, zinc oxide, fine particles and ultrafine particles ofzinc oxide, alumina, silica, fumed silica (ultrafine particulate silicicanhydride), mica titanium, fish scale guanine, boron nitride,photochromic pigment, synthetic fluorophlogopite, fine particles ofcompound powder, gold, and aluminum; inorganic powder such as powderhydrophobized or hydrophilized by treating the above-listed inorganicpowder using various surface treating agents, such as silicone such ashydrogen silicone or cyclic hydrogen silicone, or otherwise, othersilane, or a titanium coupling agent; and organic powder,surface-treated powder, and organic-inorganic compound powder havingvarious sizes and shapes, such as starch, cellulose, nylon powder,polyethylene powder, poly(methyl methacrylate) powder, polystyrenepowder, copolymer resin powder of styrene and acrylic acid, polyesterpowder, benzoguanamine resin powder, powder having layers ofpolyethylene terephthalates and poly(methyl methacrylate)s, powderhaving layers of polyethylene terephthalates, aluminum, and epoxy,urethane powder, silicone powder, and Teflon (registered trademark)powder.

Preferable examples of the inorganic salts include sodiumchloride-containing salts, such as common salt, crude salt, rock salt,sea salt, and natural salt; potassium chloride; aluminum chloride;calcium chloride; magnesium chloride; bittern; zinc chloride; ammoniumchloride; sodium sulfate; aluminum sulfate; aluminum potassium sulfate(alum); aluminum ammonium sulfate; barium sulfate; calcium sulfate;potassium sulfate; magnesium sulfate; zinc sulfate; iron sulfate; coppersulfate; sodium phosphates, such as 1Na, 2Na, and 3Na phosphoric acids;potassium phosphates; calcium phosphates; and magnesium phosphates.

Preferable examples of the ultraviolet absorbers include benzoicacid-based ultraviolet absorbers, such as p-aminobenzoic acid,p-aminobenzoic acid monoglycerin ester, N,N-dipropoxy-p-aminobenzoicacid ethyl ester, N,N-diethoxy-p-aminobenzoic acid ethyl ester,N,N-dimethyl-p-aminobenzoic acid ethyl ester,N,N-dimethyl-p-aminobenzoic acid butyl ester, andN,N-dimethyl-p-aminobenzoic acid ethyl ester; anthranilic acid-basedultraviolet absorbers, such as homomenthyl N-acetylanthranilate;salicylic acid-based ultraviolet absorbers, such as salicylic acid andsodium salt thereof, amyl salicylate, menthyl salicylate, homomenthylsalicylate, octyl salicylate, phenyl salicylate, benzyl salicylate, andp-isopropanolphenyl salicylate; cinnamic acid-based ultravioletabsorbers, such as octyl cinnamate, ethyl-4-isopropyl-cinnamate, methyl2,5-diisopropyl-cinnamate, ethyl 2,4-diisopropyl-cinnamate, methyl2,4-diisopropyl-cinnamate, propyl p-methoxycinnamate, isopropylp-methoxycinnamate, isoamyl p-methoxycinnamate, 2-ethylhexylp-methoxycinnamate (octyl p-methoxycinnamate), 2-ethoxyethylp-methoxycinnamate (cinoxate), cyclohexyl p-methoxycinnamate, ethylα-cyano-β-phenyl-cinnamate, 2-ethylhexyl α-cyano-β-phenylcinnamate(octocrylene), glyceryl mono-2-ethylhexanoyl-di-p-methoxycinnamate, andferulic acid and derivatives thereof; benzophenone-based ultravioletabsorbers, such as 2,4-dihydroxybenzophenone,2,2′-dihydroxy-4-methoxybenzophenone,2,2′-dihydroxy-4,4′-dimethoxybenzophenone,2,2′,4,4′-tetrahydroxybenzophenone, 2-hydroxy-4-methoxybenzophenone(oxybenzone-3), 2-hydroxy-4-methoxy-4′-methylbenzophenone,2-hydroxy-4-methoxybenzophenone 5-sulfonate, 4-phenylbenzophenone,2-ethylhexyl-4′-phenyl-benzophenone-2-carboxylate,2-hydroxy-4-n-octoxybenzophenone, and 4-hydroxy-3-carboxybenzophenon;3-(4′-methylbenzylidene)-d, 1-camphor; 3-benzylidene-d, 1-camphor;2-phenyl-5-methylbenzoxazole; 2,2′-hydroxy-5-methylphenylbenzotriazole;

2-(2′-hydroxy-5′-t-octylphenyl)benzotriazole;2-(2′-hydroxy-5′-methylphenyl)benzotriazole; dibenzalazine;dianisoylmethane; 5-(3,3-dimethyl-2-norbornylidene)-3-pentan-2-one;dibenzoylmethane derivatives, such as 4-t-butylmethoxydibenzoylmethane;octyltriazone; urocanic acid derivatives, such as urocanic acid andethyl urocanate; 2-(2′-hydroxy-5′-methylphenyl)benzotriazole;1-(3,4-dimethoxyphenyl)-4,4-dimethyl-1,3-pentanedione; hydantoinderivatives, such as 2-ethylhexyl dimethoxybenzylidenedioxoimidazolidine propionate; phenylbenzimidazole sulfonic acid;terephthalylidene dicamphor sulfonic acid; drometrizole trisiloxane;methyl anthranilate; rutin and derivatives thereof; and orizanol andderivatives thereof.

Preferable examples of the whitening agents include hydroquinoneglycoside, such as arbutin and a-arbutin, and esters thereof; ascorbicacid derivatives, such as ascorbic acid, ascorbic acid phosphate estersalts such as ascorbic acid phosphate sodium salt and ascorbic acidphosphate magnesium salt, ascorbic acid fatty acid esters such asascorbic acid tetraisopalmitate ester, ascorbic acid alkyl ethers suchas ascorbic acid ethyl ether, ascorbic acid glucoside such as ascorbicacid-2-glucoside and fatty acid ester thereof, ascorbic acid sulfateester, and ascorbyl tocopheryl phosphate; kojic acid; ellagic acid,tranexamic acid and derivatives thereof; ferulic acid and derivativesthereof; placenta extract; glutathione; oryzanol; butyl resorcinol; andplant extracts, such as oil-soluble chamomilla extract, oil-solublelicorice extract, Tamarix chinensis extract, and Saxifraga sarmentosaextract.

Preferable examples of the vitamins and derivatives thereof includevitamin A, such as retinol, retinol acetate, and retinol palmitate;vitamin B group, such as thiamine hydrochloride salt, thiamine sulfatesalt, riboflavin, riboflavin acetate, pyridoxine hydrochloride,pyridoxine dioctanoate, pyridoxine dipalmitate, flavin adeninedinucleotide, cyanocobalamin, folic acids, nicotinic acids, such asnicotinic-acid amide and benzyl nicotinate, and cholines; vitamin Cgroup, such as ascorbic acid and salts thereof, such as a sodium salt;vitamin D; vitamin E group, such as α-, β-, γ-, and δ-tocopherols; othervitamins, such as pantothenic acid and biotin; ascorbic acidderivatives, such as ascorbic acid phosphate ester salts such asascorbic acid phosphate ester sodium salt and ascorbic acid phosphateester magnesium salt, ascorbic acid fatty acid esters such as ascorbicacid tetraisopalmitate ester, ascorbyl stearate, ascorbyl palmitate, andascorbyl dipalmitate, ascorbic acid alkyl ethers such as ascorbic acidethyl ether, ascorbic acid glucoside, such as ascorbic acid-2-glucosideand fatty acid ester thereof, and ascorbyl tocopheryl phosphate; vitaminderivatives, such as tocopherol derivatives such as tocopherolnicotinate, tocopherol acetate, tocopherol linoleate, tocopherolferulate, and tocopherol phosphate ester; tocotrienol; and variousvitamin derivatives.

Preferable examples of the hair growth drugs, the blood circulationaccelerators, the stimulant include plant extracts/tinctures, such asSwertia japonica extract, capsicum tincture, ginger tincture, gingerextract, and cantharis tincture; capsaicin; nonylic acid vanillylamide;zingerone; ichthammol; tannic acid; borneol; cyclandelate; cinnarizine;tolazoline; acetylcholine; verapamil; cepharanthine; γ-oryzanol; vitaminE and derivatives thereof, such as tocopherol nicotinate and tocopherolacetate; γ-oryzanol; nicotinic acid and derivatives thereof, such asnicotinic amide, benzyl nicotinate ester, inositol hexanicotinate, andnicotinic alcohol; allantoin; photosensitive element 301; photosensitiveelement 401; carpronium chloride; pentadecanoic acid monoglyceride;flavanonol derivatives; stigmasterol or stigmastanol and glycosidethereof; and minoxidil.

Preferable examples of the hormones include estradiol, estrone,ethinylestradiol, cortisone, hydrocortisone, and prednisone. Preferableexamples of other medical agents, such as the anti-wrinkle agents, theanti-aging agents, the tightening agents, the cooling agents, thewarming agents, the wound healing accelerators, the irritation reducingagents, the analgesics, and the cell activators, include retinols,retinoic acids, and tocopheryl retinoate; lactic acid, glycolic acid,gluconic acid, fruit acid, salicylic acid, and, for example, glycosidesand esterified compounds thereof; α- or 3-hydroxy acids and derivativesthereof, such as hydroxycapric acid, long-chain α-hydroxy fatty acid,and long-chain α-hydroxy fatty acid cholesteryl; γ-amino butyric acidand γ-amino-β-hydroxy butyric acid; carnitine; carnosine; creatine;ceramides and sphingosines; caffeine, xanthin, and the like, andderivatives thereof; antioxidants/active oxygen eliminating agents, suchas coenzyme Q10, carotene, lycopene, astaxanthin, lutein, α-lipoic acid,platinum nanocolloid, and fullerenes; catechins; flavones, such asquercetin; isoflavones; gallic acid and ester sugar derivatives thereof;polyphenols, such as tannin, sesamin, protoanthocyanidin, chlorogenicacid, and apple polyphenols; rutin and derivatives thereof, such asglycosides thereof; hesperidin and derivatives thereof, such asglycosides thereof; lignan glycoside; substances related to licoriceextract, such as glabridin, glabrene, liquiritin, and isoliquiritin;lactoferrin; shogaol and gingerol; fragrance materials, such as mentholand cedrol, and derivatives thereof; capsaicin, vanillin, and the like,and derivatives thereof; insect repellents, such as diethyltoluamide;complexes of biologically active substances and cyclodextrin.

Preferable examples of the plant/animal/microbial extracts includeextracts, such as iris extract, Angelica keiskei extract, Thujopsisdolabrata extract, asparagus extract, avocado extract, Hydrangea serrataleaf extract, almond extract, althea extract, arnica extract, aloeextract, apricot extract, apricot kernel extract, Ginkgo biloba extract,Artemisia capillaris flower extract, fennel fruit extract, turmeric rootextract, oolong tea extract, uva-ursi extract, Rosa multiflora fruitextract, Echinacea angustifolia leaf extract, isodon japonicus extract,Scutellaria baicalensis root extract, phellodendron bark extract, coptisrhizome extract, barley extract, panax ginseng extract, Hypericumerectum extract, Lamium album extract, Ononis spinosa extract,Nasturtium officinale extract, orange extract, dried sea water residues,sea weed extract, persimmon leaf extract, Pyracantha fortuneana fruitextract, hydrolyzed elastin, hydrolyzed wheat flour, hydrolyzed silk,pueraria root extract, Chamomile extract, oil-soluble Chamomile extract,carrot extract, Artemisia capillaris flower extract, oat extract,karkade extract, licorice extract, oil-soluble licorice extract, kiwifruit extract, senecio extract, Auricularia auricula extract, cinchonabark extract, cucumber extract, paulownia tomentosa leaf extract,guanosine, guava extract, sophora root extract, gardenia extract, Sasaveitchii extract, Sophora angustifolia root extract, walnut extract,Japanese chestnut extract, grapefruit extract, clematis extract, blackrice extract, brown sugar extract, black vinegar, chlorella extract,Mulberry extract, Gentiana lutea extract, Geranium nepalense sweetextract, black tea extract, yeast extract, Magnolia cortex extract,coffee extract, burdock extract, rice extract, fermented rice extract,fermented rice bran extract, rice germ oil, comfrey extract, collagen,Vaccinium vitis-idaea extract, Asiasarum root extract, bupleurum rootextract, umbilical extract, saffron extract, salvia extract, Saponariaofficinalis extract, Sasa bamboo grass extract, Crataegus cuneata fruitextract, Bombyx mori extract, Zanthoxylum piperitum peel extract,shiitake extract, Rehmannia chinensis extract, Lithospermumerythrorhizon root extract, Perilla extract, Tilia cordata flowerextract, spiraea ulmaria flower extract, Jatoba extract, Paeonialactiflora extract, Zingiber officinale extract, Acorus calamus rootextract, Betula alba extract, Tremella fusiformis extract, Equisetumarvense extract, Stevia rebaudiana extract, fermentated products ofStevia rebaudiana, Tamarix chinensis extract, Hedera helix extract,Crataegus oxyacantha extract, Sambucus nigra extract, Achilleamillefolium extract, Mentha piperita extract, sage extract, Malvasylvestris extract, Cnidium officinale root extract, Swertia japonicaextract, mulberry bark extract, rhubarb extract, soybean extract, jujubeextract, thyme extract, dandelion extract, lichen extract, tea extract,Eugenia caryophyllus flower extract, Imperata cylindrica root extract,citrus unshiu peel extract, tea tree oil, Rubus suavissimus extract, redpepper extract, angelica root extract, Calendula officinalis extract,peach kernel extract, bitter orange peel extract, Houttuynia cordataextract, tomato extract, fermented soybean extract, ginseng extract,garlic extract, Rosa canina fruit extract, hibiscus extract, Ophiopogontuber extract, Nelumbo nucifera extract, parsley extract, birch extract,honey, hamamelis extract, Parietaria officinalis extract, Isodonisjaponicus extract, bisabolol, Chamaecyparis obtusa extract,Lactobacillus bifidus extract, Eriobotrya japonica extract, coltsfootextract, Petasites japonicus extract, Poria cocos extract, butcher'sbroom extract, grape extract, grape seed extract, propolis, Luffacylindrica fruit extract, safflower extract, peppermint extract, Tiliaplatyphyllos flower extract, Paeonia suffruticosa root extract, Humuluslupulus extract, Rosa rugosa flower extract, pine cone extract, horsechestnut extract, Asian skunk-cabbage extract, Sapindus mukorossi peelextract, melissa extract, Cladosiphon okamuranus extract, peach extract,Centaurea cyanus flower extract, eucalyptus extract, Saxifragasarmentosa extract, Citrus junos fruit extract, lily extract, coix seedextract, Artemisia princeps extract, lavender extract, green teaextract, eggshell membrane extract, apple extract, rooibos tea extract,lychee extract, lettuce extract, lemon extract, Forsythia extract,Astragalus sinicus extract, rose extract, rosemary extract, Anthemisnobilis flower extract, royal jelly extract, and Sanguisorba officinalisroot extract,

Examples of the antipruritic agents include diphenhydraminehydrochloride, chlorpheniramine maleate, camphor, and a substance-Pinhibitor.

Examples of the corneum releasing/dissolving agents include salicylicacid, sulfur, resorcin, selenium sulfide, and pyridoxine.

Examples of the antiperspirants include chlorohydroxyaluminum, aluminumchloride, zinc oxide, and zinc p-phenolsulfonate.

Examples of the refrigerants include menthol and methyl salicylate.

Examples of the astringent agents include citric acid, tartaric acid,lactic acid, aluminum potassium sulfate, and tannic acid.

Examples of the enzymes include superoxide dismutase, catalase, lysozymechloride, lipase, papain, pancreatin, and protease.

Preferable examples of the nucleic acids include ribonucleic acids andsalts thereof, deoxyribo nucleic acids and salts thereof, and adenosinetriphosphate disodium.

Preferable examples of the fragrances include synthetic fragrances,natural fragrances, and various blended fragrances, such as acetylcedrene, amylcinnamaldehyde, allyl amyl glycolate, β-ionone, Iso ESuper, isobutylquinoline, iris oil, irone, indole, ylang ylang oil,undecanal, undecenal, γ-undecalactone, estragole, eugenol, oakmoss,Opoponax resinoid, orange oil, eugenol, aurantiol, galaxolide,carvacrol, 1-carvone, camphor, canon, carrot seed oil, clove oil, methylcinnamate, geraniol, geranyl nitrile, isobornyl acetate, geranylacetate, dimethylbenzylcarbinyl acetate, styralyl acetate, cedrylacetate, terpinyl acetate, p-t-butylcyclohexyl acetate, vetiverylacetate, benzyl acetate, linalyl acetate, isopentyl salicylate, benzylsalicylate, sandal wood oil, santalol, cyclamen aldehyde,cyclopentadecanolide, methyl dihydrojasmonate, dihydromyrcenol, jasmineabsolute, jasmine lactone, cis-jasmone, citral, citronellol,citronellal, cinnamon bark oil, 1,8-cineole, cinnamaldehyde, styraxresinoid, cedar wood oil, cedrene, cedrol, celery seed oil, thyme oil,damascone, damascenone, thymol, tuberose absolute, decanal, decalactone,terpineol, γ-terpinene, triplal, nerol, nonanal, 2,6-nonadienol,nonanolactone, patchouli alcohol, vanilla absolute, vanillin, basil oil,patchouli oil, hydroxycitronellal, α-pinene, piperitone, phenethylalcohol, phenylacetaldehyde, petitgrain oil, hexylcinnamaldehyde,cis-3-hexenol, Peruvian balsam, vetiver oil, vetiverol, peppermint oil,pepper oil, heliotropin, bergamot oil, benzyl benzoate, borneol, myrrhresinoid, musk ketone, methyl nonyl acetaldehyde, γ-methylionone,menthol, 1-menthol, 1-menthone, eucalyptus oil, β-ionone, lime oil,lavender oil, d-limonene, linalool, lyral, lilial, lemon oil, roseabsolute, rose oxide, rose oil, rosemary oil, and various essentialoils.

Preferable examples of the dyestuffs, the colorants, the dyes, thepigments include legal dyestuffs, such as Brown No. 201, Black No. 401,Violet No. 201, Violet No. 401, Blue No. 1, Blue No. 2, Blue No. 201,Blue No. 202, Blue No. 203, Blue No. 204, Blue No. 205, Blue No. 403,Blue No. 404, Green No. 201, Green No. 202, Green No. 204, Green No.205, Green No. 3, Green No. 401, Green No. 402, Red No. 102, Red No.104-1, Red No. 105-1, Red No. 106, Red No. 2, Red No. 201, Red No. 202,Red No. 203, Red No. 204, Red No. 205, Red No. 206, Red No. 207, Red No.208, Red No. 213, Red No. 214, Red No. 215, Red No. 218, Red No. 219,Red No. 220, Red No. 221, Red No. 223, Red No. 225, Red No. 226, Red No.227, Red No. 228, Red No. 230-1, Red No. 230-2, Red No. 231, Red No.232, Red No. 3, Red No. 401, Red No. 404, Red No. 405, Red No. 501, RedNo. 502, Red No. 503, Red No. 504, Red No. 505, Red No. 506, Orange No.201, Orange No. 203, Orange No. 204, Orange No. 205, Orange No. 206,Orange No. 207, Orange No. 401, Orange No. 402, Orange No. 403, YellowNo. 201, Yellow No. 202-1, Yellow No. 202-2, Yellow No. 203, Yellow No.204, Yellow No. 205, Yellow No. 4, Yellow No. 401, Yellow No. 402,Yellow No. 403-1, Yellow No. 404, Yellow No. 405, Yellow No. 406, YellowNo. 407, and Yellow No. 5; other acid dyes, such as Acid Red 14; basicdyes, such as Arianor Sienna Brown, Arianor Madder Red, Arianor SteelBlue, and Arianor Straw Yellow; nitro dyes, such as HC Yellow 2, HCYellow 5, HC Red 3,4-hydroxypropylamino-3-nitrophenol,N,N′-bis(2-hydroxyethyl)-2-nitro-p-phenylenediamine, HC Blue 2, andBasic Blue 26; disperse dyes; inorganic white pigments, such as titaniumdioxide and zinc oxide; inorganic red-based pigments, such as iron oxide(red iron oxide) and iron titanate; inorganic brown-based pigments, suchas γ-ferric oxide; inorganic yellow-based pigments, such as yellow ironoxide and ocher; inorganic black-based pigments, such as black ironoxide and low-order titanium oxide; inorganic violet-based pigments,such as mango violet and cobalt violet; inorganic green-based pigments,such as chromium oxide, chromium hydroxide, and cobalt titanate;inorganic blue-based pigments, such as ultramarine blue and Prussianblue; pearly pigments, such as titanium oxide-coated mica, titaniumoxide-coated bismuth oxychloride, titanium oxide-coated talc, coloredtitanium oxide-coated mica, bismuth oxychloride, and fish scale guanine;metal powder pigments, such as aluminum powder, copper powder, and gold;surface-treated inorganic and metal powder pigments; organic pigments,such as a zirconium, barium, or aluminum lake; surface-treated organicpigments; natural dyestuffs and dyes, such as anthraquinones such asastaxanthin and alizarin, naphthoquinones such as anthocyanidin,β-carotene, catenar, capsanthin, chalcone, carthamin, quercetin, crocin,chlorophyll, curcumin, cochineal, and shikonin, bixin, flavones,betacyanidin, henna, hemoglobin, lycopene, riboflavin, and rutin;oxidation dye intermediates and couplers, such as p-phenylenediamine,toluene-2,5-diamine, o-, m-, or p-aminophenol, m-phenylenediamine,5-amino-2-methylphenol, resorcin, 1-naphthol, and 2,6-diaminopyridine,and salts thereof; auto-oxidation type dyes, such as indoline; anddihydroxyacetone.

Preferable examples of the antiphlogistic agents and theantiinflammatory agents include glycyrrhizic acid and derivativesthereof, glycyrrhetic acid derivatives, salicylic acid derivatives,hinokitiol, guaiazulene, allantoin, indomethacin, ketoprofen, ibuprofen,diclofenac, loxoprofen, celecoxib, infliximab, etanercept, zinc oxide,hydrocortisone acetate, prednisone, diphenhydramine hydrochloride,chlorpheniramine maleate, and plant extracts such as peach leaf extractand Artemisia princeps leaf extract.

Preferable examples of the antiasthmatic agents, the anti-chronicobstructive pulmonary disease agents, the antiallergic agents, and theimmunomodulators include aminophylline, theophyllines, steroids (such asfluticasone and beclomethasone), leukotriene antagonists, thromboxaneinhibitors, Intal, β-2 stimulants (such as formoterol, salmeterol,albuterol, tulobuterol, clenbuterol, epinephrine), tiotropium,ipratropium, dextromethorphan, dimemorfan, bromhexine, tranilast,ketotifen, azelastine, cetirizine, chlorpheniramine, mequitazine,tacrolimus, cyclosporine, sirolimus, methotrexate, cytokine regulatingagents, interferon, omalizumab, and protein/antibody formulations.

Preferable examples of the anti-infective agents and the antifungalagents include oseltamivir, zanamivir, and itraconazole. Themoisturizing base material can contain, in addition to the above-listedingredients, known ingredients for cosmetics, pharmaceutical products,and foods, such as ingredients listed in, for example, the JapaneseStandards of Cosmetic Ingredients, the Japanese Cosmetic IngredientsCodex, the Japan Cosmetic Industry Association's list of displayed namesof ingredients, the International Cosmetic Ingredient Dictionary andHandbook (INCI Dictionary), the Japanese Standards of Quasi-drugIngredients, the Japanese Pharmacopoeia, the Japanese PharmaceuticalExcipients, and the Japan's Specifications and Standards for FoodAdditives, and ingredients listed in patent publications and unexaminedpatent publications (including published and re-published Japanesetranslation of PCT international applications) of Japan and variousother countries that are classified in classes A61K7 and A61K8 of theInternational Patent Classification (IPC), in known combinations and atknown blending ratios or blending amounts.

[Production Method of Transdermally Absorbable Base Material (1)]

The transdermally absorbable base material of the present invention canbe produced by mixing and stirring under heat, the lipid peptidecompound including at least one of the compounds of Formulae (1) to (3)above or pharmaceutically usable salts thereof, the surfactant, the1,2-alkanediol or the glycerin, at least one fatty acid, water, andfurthermore, as desired, the oleaginous base material, the organic acid,and the other additives, and then leaving the mixture at rest to becooled. The premix for the transdermally absorbable base material can beproduced in this production process, as will be described later.

For example, the transdermally absorbable base material of the presentinvention is produced, as an example, by the following processes.

a) A process of blending the lipid peptide compound with the surfactant,the 1,2-alkanediol or the glycerin, at least one fatty acid, and water,and heating the mixture to prepare a solution or a dispersion liquid;

b) a process of adding the solution or the dispersion liquid to thewater, and heating the mixture at a temperature of room temperature orhigher and lower than 100° C.; and

c) a process of cooling while stirring the mixture to a temperaturelower than that in the heating process, and then leaving the mixture atrest to be cooled to be formed into a gelatinous solid (transdermallyabsorbable base material).

The oleaginous base material, the organic acid, and the other additivesmay be added in the preparation process of the solution or thedispersion liquid in the process a), or may be added in advance to thewater to which the solution or the dispersion liquid is to be added inthe process b). Moreover, the surfactant can be blended, instead of inthe process a), in the subsequent process b).

The content of the water is preferably 50% by mass or higher and lowerthan 95% by mass with respect to the total mass of the obtainedtransdermally absorbable base material.

The content of the water is preferably 50% by mass or higher and lowerthan 80% by mass with respect to the total mass of the solution or thedispersion liquid obtained.

The heating temperature in the processes a) and b) is preferably from50° C. to 90° C., and more preferably from 60° C. to 90° C., such as 80°C. The mixture is preferably stirred while being heated. While the timeof heating and stirring in each of the processes depends on the typesand blending amounts of the lipid peptide compound, the surfactant, andother ingredients used, the dissolution or dispersion can be normallycompleted in roughly 5 minutes to 50 minutes.

Subsequently to the processes a) and b), the mixture is cooled whilebeing stirred until the liquid temperature reaches a temperature lowerthan that in the process b) (process c)). The cooling temperature inthis process is, for example, roughly between room temperature and 80°C., between room temperature and 60° C., or between room temperature and40° C.

[Production Methods of Premix and Transdermally Absorbable Base Material(2)]

The following describes a production method of the transdermallyabsorbable base material using the premix of the present invention.

As will be described in detail below, the premix is produced through theprocess a) of [Production method of transdermally absorbable basematerial (1)] described above.

<Production Method of Premix>

To produce the premix, first, the lipid peptide compound including atleast one of the compounds of Formulae (1) to (3) above orpharmaceutically usable salts thereof, the surfactant, the1,2-alkanediol or the glycerin, at least one fatty acid, and water aremixed together, and are heated to prepare the solution or the dispersionliquid. During the preparation of the solution or the dispersion liquid,the oleaginous base material, the organic acid, and the other additivescan be added as desired.

The premix can be obtained by cooling the solution or the dispersionliquid.

The temperature of the above-described heating is preferably from 50° C.to 90° C., and more preferably from 60° C. to 90° C., such as 80° C. Themixture is preferably stirred while being heated. While the time of theheating (stirring) depends on the lipid peptide compound used, the typesof the surfactant and other ingredients, and the blending amounts ofthese ingredients, the time is roughly 5 minutes to 50 minutes, afterwhich the solution or the dispersion liquid in which the blendedingredients are dissolved or dispersed is obtained.

The solution or the dispersion liquid thus obtained is preferably cooledwhile being stirred to a temperature lower than the above-describedheating temperature, for example, to a temperature roughly between roomtemperature and 80° C., between room temperature and 60° C., or betweenroom temperature and 40° C., and then preferably stops being stirred tobe left at rest.

The content of the water is preferably 50% by mass or higher and lowerthan 80% by mass with respect to the total mass of the obtained premix.

The premix thus obtained is useful as a premix for preparing thetransdermally absorbable base material. The transdermally absorbablebase material can be easily prepared by blending water and othereffective ingredients with the premix, as will be described later.

<Production Method of Transdermally Absorbable Base Material UsingPremix>

The transdermally absorbable base material can be produced through, forexample, the following processes 1) to 3) using the premix of thepresent invention thus obtained.

1) A process of heating the premix at a temperature of room temperatureor higher and lower than 100° C.;

2) a process of adding the above-described heated premix to an aqueousphase heated at a temperature of room temperature or higher and lowerthan 100° C., and mixing the mixture; and

3) a process of cooling the obtained mixture to form a gel.

The above-described aqueous phase contains water, can further containthe oleaginous base material, and may contain the organic acid and theother additives.

In the case of blending the organic acid with the transdermallyabsorbable base material, the transdermally absorbable base materialblended with the organic acid can be produced through, for example, thefollowing processes 4) to 7).

4) A process of heating the premix at a temperature of room temperatureor higher and lower than 100° C.;

5) a process of adding the above-described heated premix to an aqueousphase heated at a temperature of room temperature or higher and lowerthan 100° C., and mixing the mixture;

6) a process of cooling the obtained mixture to form a gel; and

7) a process of adding a mixed solution of water and the organic acid tothe above-described mixture and further mixing the resultant mixtureduring the above-described cooling process.

The above-described aqueous phase contains water, can further containthe oleaginous base material, and may further contain the otheradditives.

The heating temperature of the premix in the above-describedprocesses 1) and 4) is preferably from 50° C. to 90° C., and morepreferably from 60° C. to 90° C., such as 70° C. or 80° C. Theseprocesses are preferably performed while the stirring is performed.While the time of heating (stirring) in each of the processes depends onthe types and blending amounts of the lipid peptide compound, thesurfactant, and the other additives contained in the premix, the time isnormally roughly 5 minutes to 50 minutes. These processes bring thepremix into a uniformly dissolved state.

The heating temperature of the aqueous phase in the above-describedprocesses 2) and 5) is preferably from 50° C. to 90° C., and morepreferably from 60° C. to 90° C., such as 70° C. or 80° C. The aqueousphase is preferably heated while being stirred, particularly if theaqueous phase contains the other ingredients, such as the oleaginousbase material. If the aqueous phase contains the oleaginous basematerial and the other ingredients, the heating (stirring) is preferablyperformed normally for roughly 5 minutes to 50 minutes until theseingredients are uniformly dissolved or dispersed. The heatingtemperature of the aqueous phase may be the same as that of the premix.

Subsequently, in each of the above-described processes 3) and 6), themixture obtained in the previous process is cooled to form a gel. Atthis time, the mixture may be cooled while being stirred. If the mixtureis cooled while being stirred, the mixture is preferably stirred untilthe cooling temperature reaches, for example, a temperature between roomtemperature and 80° C. or between room temperature and 60° C., such asroughly 60° C., and then preferably stops being stirred to be left atrest and cooled. The mixture preferably stops being stirred to be leftat rest and cooled, particularly when the temperature is 50° C. orlower.

If the transdermally absorbable base material contains an organic acidsuch as ascorbic acid, the above-described process 6) (cooling process)includes a process of adding a mixed solution of water and the organicacid to the mixture and further mixing the resultant mixture.

In this process, the mixed solution of water and the organic acid to beadded preferably has roughly the same temperature as that of the mixtureto which the mixed solution is to be added so as to achieve uniformmixing. The mixed solution may contain the oleaginous base material andthe other additives as desired, and may be heated (stirred) at anappropriate temperature until those ingredients are uniformly dissolvedor dispersed.

For example, when the liquid temperature of the mixture has reachedroughly 60° C. while being stirred in the above-described process 6),the mixed solution of water and the organic acid having the liquidtemperature of roughly 60° C. is added to the mixture, and further mixedto make the system of mixture uniform. Then, the mixture preferablystops being stirred to be left at rest and cooled to obtain the gel(transdermally absorbable base material).

Also in the transdermally absorbable base material thus obtained usingthe premix, the blending amount of the water is preferably 50% by massor higher and lower than 95% by mass with respect to the total mass ofthe transdermally absorbable base material.

EXAMPLES

The present invention will be described in detail by way of examples andtest examples, but is not limited to these examples.

Synthesis Example 1: Synthesis of Lipid Peptide (N-palmitoyl-Gly-His)

A lipid peptide used as a gelator in examples was synthesized using amethod described below.

Into a four-necked flask of 500 mL, 14.2 g (91.6 mmol) of histidine,30.0 g (91.6 mmol) of N-palmitoyl-Gly-methyl, and 300 g of toluene werecharged, and 35.3 g (183.2 mmol) of a 28% methanol solution of sodiummethoxide as a base was added thereto. The mixture was heated to 60° C.in an oil bath, and stirred for 1 hour. Then, the oil bath was removed,and the solution was left standing to be cooled to 25° C. and wassubjected to reprecipitation using 600 g of acetone to collect a solidby filtration. The solid obtained here was dissolved in a mixed solutionof 600 g of water and 750 g of methanol. To the mixed solution, 30.5 mL(183.2 mmol) of 6N hydrochloric acid was added to neutralize thesolution and precipitate a solid, which was then filtered. Then, theobtained solid was dissolved in a mixed solution of 120 g oftetrahydrofuran and 30 g of water at 60° C., and 150 g of ethyl acetatewas added thereto. The mixture was cooled from 60° C. to 30° C. Then,the precipitated solid was collected by filtration. Furthermore, theobtained solid was dissolved in a solvent of 120 g of tetrahydrofuranand 60 g of acetonitrile. The solution was heated to 60° C., stirred for1 hour, then cooled, and filtered. The solid thus obtained was washedwith 120 g of water, filtered, and then dried under reduced pressure toobtain 26.9 g of white crystals of a free form of N-palmitoyl-Gly-His(hereinafter, also simply called Pal-GH) (at a yield of 65%).

Example 1: Preparation of Premix

The Pal-GH obtained in the synthesis example 1 above, 1,2-hexanediol,polyoxyethylene lauryl ether, stearic acid, and water were weigh out soas to form a composition (% by mass) illustrated in Table 1, and chargedinto a sample tube (No. 7 manufactured by Maruemu Corporation). Themixture was heated and stirred at 80° C. to obtain a Pal-GH dispersionliquid (premix). The stirring was performed at 200 rpm using LABORATORYHIGH MIXER manufactured by AS ONE Corporation.

TABLE 1 Ingredient Premix composition (% by mass) Pal-GH 10.01,2-hexanediol *¹ 4.0 Polyoxyethylene lauryl ether *² 8.0 Stearic acid*³ 1.0 Water Rest *¹ manufactured by ITO Inc. *² manufactured by NikkoChemicals Co., Ltd. [product name: NIKKOL BL 4.2, POE (4.2) laurylether] *³ manufactured by Kao Corporation [product name: S-98]

Examples 2 to 4 and Comparative Example 1: Preparation of TransdermallyAbsorbable Base Material Using Premix

According to Table 2 below, Phase A (premix prepared in Example 1) wasweighed out into a sample tube No. 5, and heated in a water bath (at aset temperature of 85° C.) to be uniformly dissolved.

The ingredients of Phase B were weighed out into another Maruemu sampletube No. 5 having therein a stirrer chip, and heated in a water bath (ata set temperature of 85° C.). Phase A was added to Phase B, mixed whilebeing heated and stirred for roughly 30 seconds. Then, the mixture wascooled while being stirred until the liquid temperature reached roughly60° C.

For each of Examples 2 and 3, the ingredients of Phase C were weighedout into still another sample tube No. 5, and heated to a liquidtemperature of roughly 60° C. When the liquid temperature of mixture ofPhase A and Phase B described above reached 60° C., Phase C having aliquid temperature of roughly 60° C. was added thereto, and the mixturewas stirred for roughly 30 seconds, and then left at rest and cooled tobe formed into a gel (transdermally absorbable base material).

For each of Example 4 and Comparative Example 1, after the liquidtemperature reached roughly 60° C., the mixture was left at rest andcooled to be formed into a gel (transdermally absorbable base material).

TABLE 2 Exam- Exam- Exam- Comparative Ingredient (g) ple 2 ple 3 ple 4Example 1 Phase A Premix 5 5 50 1.0 wt % 50 Carbopol *⁴ Phase BFluorescently- 20 20 20 20 labeled 1.0 wt % hyaluronic acid aqueoussolution *⁵ 1,3-butanediol *⁶ 20 20 Squalane *⁷ 10 1M NaOH *⁸ 2 10%Tween 20 5 aqueous solution *⁹ Water 30 15 30 28 Phase C 40 wt % citricacid 25 25 solution *¹⁰ *⁴ manufactured by Nikko Chemicals Co., Ltd. *⁵manufactured by Kewpie Corporation [product name: Hyalo-Oligo(registered trademark)] *⁶ manufactured by Wako Pure Chemical IndustriesLtd. *⁷ manufactured by Wako Pure Chemical Industries Ltd. [productname: Squalane] *⁸ manufactured by Nacalai Tesque, Inc. [product name: 1mol/L-sodium hydroxide solution] *⁹ manufactured by Tokyo ChemicalIndustry Co., Ltd. [product name: Tween #20] *¹⁰ manufactured by WakoPure Chemical Industries Ltd. [prepared using citric acid monohydrate]

Example 5: Skin Permeability Test of Transdermally Absorbable BaseMaterial

Yucatan Micro Pig (YMP) skin (by Charles River Laboratories Japan, Inc.)stored at −80° C. was thawed at room temperature (roughly 25° C.), andwas then subjected to the fat removal (to have a skin thickness ofroughly 2 mm). Thus, the YMP skin of roughly 2 cm square was prepared.

To a receiver phase of a vertical Franz type diffusion cell (effectivearea: 0.785 cm²), 5.0 mL of phosphate buffered saline (PBS of pH 7.4,stirred at 500 rpm) was added, and the above-described YMP skin(temperature of PBS on skin surface: 32.5° C.) was set. Each of the gels(200 mg) prepared in Example 4 and Comparative Example 1 was placed inthe donor phase of the vertical Franz type diffusion cell (refer to FIG.2).

The skin was taken out after 24 hours, and washed with an extractant[solution of PBS, acetonitrile, and methanol mixed at 2:1:1 (v/v/v)].The liquid on the skin surface was wiped out with KimWipes (registeredtrademark). Then, the skin was cut into small pieces (16 pieces) with autility knife, and put into a light-shielding microtube, to which 0.5 mLof the above-described extractant was added. The mixture was stirredwith a vortex mixer for three hours, and fluorescently-labeledhyaluronic acid in the skin was extracted. The extracted solution thusobtained was filtered using a PTFE filter (0.45 μm), and then, thequantity of the fluorescently-labeled hyaluronic acid in the solutionwas determined using a fluorescence spectrometer LS-55 (manufactured byPerkinElmer, Inc.) (each calculated as the average value of threetests). The fluorescence spectrometer measurement was made at anexcitation wavelength of 495 nm and a measurement wavelength of 521 nm.FIG. 1 illustrates the results obtained.

As illustrated in FIG. 1, the results were obtained, showing that thetransdermally absorbable base material of Example 4 surpasses thetransdermally absorbable base material of Comparative Example 1 intransdermal absorption of hyaluronic acid by a factor of roughly 3.

In this way, the result shows that the transdermally absorbable basematerial of the present invention is useful as a transdermallyabsorbable base material excellent in the transdermal absorbabilitythereof when the active ingredients, such as hyaluronic acid, areblended therewith.

Moreover, as described below, the transdermal absorbability was testedfor the transdermally absorbable base material of the present inventionor transdermally absorbable base materials containing an oleaginouscomponent (isopropyl myristate (IPM)) of the present invention wheninsulin was blended as an active ingredient. Commercially availableinsulin manufactured by Sigma-Aldrich Corporation and the followingprepared insulin were used as the fluorescently-labeled insulin.

Preparation Example 1: Preparation of Fluorescently-Labeled InsulinAqueous Solution

Insulin/carbonic acid buffer (15 mg/mL) was prepared as described below.30 mg of insulin (insulin from bovine pancreas (lot number: 016K1256)manufactured by Sigma-Aldrich Corporation) was dissolved in 2 mL of 0.1M carbonic acid buffer (pH 9) over several days. 250 μL of FITC/DMSO (20mg/mL) was prepared (FITC: fluorescein-5-isothiocyanate manufactured byMolecular Probes, Inc.). Under the shaded condition, a total of 250 μLof the FITC/DMSO solution was added 10 μL at a time while the insulinwas slowly stirred. Under the shaded condition, the solution was reactedat 4° C. to 10° C. for roughly two nights. The solution was refinedusing a PD-10 column, and an FITC-labeled insulin aqueous solution wasobtained. The protein density was calculated using a BCA assay; the FITCdensity was calculated using an absorbance method; and the labelingratio was calculated.

With a labeling ratio of 0.733909, 3.334969 mg/ml of the FITC-labeledinsulin aqueous solution was obtained.

Examples 6 and 7 and Comparative Example 2: Preparation of TransdermallyAbsorbable Base Material Using Premix

According to Table 3 below, Phase A (premix prepared in Example 1) wasweighed out into a sample tube No. 5, and heated in a water bath (at aset temperature of 85° C.) to be uniformly dissolved.

The ingredients of Phase B were weighed out into another Maruemu sampletube No. 5 having therein a stirrer chip, and heated in a water bath (ata set temperature of 85° C.). Phase A was added to Phase B, mixed whilebeing heated and stirred for roughly 30 seconds. Then, the mixture wascooled while being stirred until the liquid temperature reached roughly60° C.

For each of Examples 6 and 7, the ingredients of Phase C were weighedout into still another sample tube No. 5, and heated to a liquidtemperature of roughly 60° C. When the liquid temperature of (PhaseA+Phase B) described above reached 60° C., Phase C having a liquidtemperature of roughly 60° C. was added thereto, and the mixture wasstirred for roughly 30 seconds, and then left at rest and cooled to beformed into a gel (transdermally absorbable base material). Each of theprepared transdermally absorbable base materials contains 0.1% by massof the fluorescently-labeled insulin (FITC-labeled insulin).

For Comparative Example 2, after the liquid temperature reached roughly60° C., the mixture was left at rest and cooled to be formed into a gel(transdermally absorbable base material).

TABLE 3 Exam- Exam- Comparative Ingredient (g) ple 6 ple 7 Example 2Phase A Premix 5 5 1.0 wt % Carbopol *¹¹ 50 Phase B 1 wt % FITC-labeled10 10 10 insulin aqueous solution *¹² 1,3-butanediol *¹³ 20 20 IPM *¹⁴10 1M NaOH *¹⁵ 0.5 10% Tween 20 5 aqueous solution *¹⁶ Water 55 40 39.5Phase C 5 wt % Mg ascorbate 10 10 aqueous solution *¹⁷ *¹¹ manufacturedby Nikko Chemicals Co., Ltd. [product name: Carbopol 940] *¹²FITC-labeled insulin manufactured by Sigma-Aldrich Corporation *¹³manufactured by ITO, Inc. [product name: 13 Butimoist] *¹⁴ manufacturedby Tokyo Chemical Industry Co., Ltd. [product name: Isopropyl Myristate]*¹⁵ manufactured by Nacalai Tesque, Inc. [product name: 1 mol/L-sodiumhydroxide solution] *¹⁶ manufactured by Tokyo Chemical Industry Co.,Ltd. [product name: Tween #20] *¹⁷ L-ascorbic acid phosphate Mg,L-ascorbic acid phosphate ester magnesium salt manufactured by Wako PureChemical Industries Ltd.

Example 8: Skin Permeability Test of Transdermally Absorbable BaseMaterial

Yucatan Micro Pig (YMP) skin (by Charles River Laboratories Japan, Inc.)stored at −80° C. was thawed at room temperature (roughly 25° C.), andwas then subjected to the fat removal (to have a skin thickness ofroughly 2 mm). Thus, the YMP skin of roughly 2 cm square was prepared.

To a receiver phase of the vertical Franz type diffusion cell (effectivearea: 0.785 cm²), 5.0 mL of phosphate buffered saline (PBS of pH 7.4,stirred at 500 rpm) was added, and the above-described YMP skin(temperature of PBS on skin surface: 32.5° C.) was set. Each of the gels(200 mg) prepared in Examples 6 and 7 and Comparative Example 2 wasplaced in the donor phase of the vertical Franz type diffusion cell(refer to FIG. 2).

The skin was taken out after 24 hours, and washed with the extractant[solution of PBS, acetonitrile, and methanol mixed at 2:1:1 (v/v/v)].The liquid on the skin surface was wiped out with KimWipes (registeredtrademark). Then, the skin was cut into small pieces (16 pieces) with autility knife, and put into a light-shielding microtube, to which 0.5 mLof the above-described extractant was added. The mixture was stirredwith the vortex mixer for three hours, and the fluorescently-labeledinsulin in the skin was extracted. Also, 1 mL of the receiver solutionof the Franz type diffusion cell was put into the light-shieldingmicrotube. The extracted solution thus obtained was filtered using aPTFE filter (0.20 μm), and then, the quantity of thefluorescently-labeled insulin in the solution was determined using thefluorescence spectrometer LS-55 (manufactured by PerkinElmer, Inc.)(each calculated as the average value of three tests). The fluorescencespectrometer measurement was made at an excitation wavelength of 495 nmand a measurement wavelength of 521 nm. FIG. 3 illustrates the resultsobtained.

As illustrated in FIG. 3, the results were obtained, showing that thetransdermally absorbable base materials of Examples 6 and 7 surpass thetransdermally absorbable base material of Comparative Example 2 intransdermal absorption of insulin. No difference was found in density(roughly 0.1 μg/cm²) of the fluorescently-labeled insulin in thereceiver solution.

In this way, the result shows that the transdermally absorbable basematerial of the present invention is useful as a transdermallyabsorbable base material excellent in the transdermal absorbabilitythereof when the active ingredients, such as insulin, are blendedtherewith.

Example 9: Skin Permeability Test of Transdermally Absorbable BaseMaterial

Yucatan Micro Pig (YMP) skin (by Charles River Laboratories Japan, Inc.)stored at −80° C. was thawed at room temperature (roughly 25° C.), andwas then subjected to the fat removal (to have a skin thickness ofroughly 2 mm). Thus, the YMP skin of roughly 2 cm square was prepared.

To a receiver phase of the vertical Franz type diffusion cell (effectivearea: 0.785 cm²), 5.0 mL of phosphate buffered saline (PBS of pH 7.4,stirred at 500 rpm) was added, and the above-described YMP skin(temperature of PBS on skin surface: 32.5° C.) was set. Each of the gels(200 mg) prepared in Examples 6 and 7 and Comparative Example 2 wasplaced in the donor phase of the vertical Franz type diffusion cell(refer to FIG. 2).

The skin was taken out after 24 hours, and washed with the extractant[solution of PBS, acetonitrile, and methanol mixed at 2:1:1 (v/v/v)].The liquid on the skin surface was wiped out with KimWipes (registeredtrademark). Then, tape stripping of the YMP skin was conducted (for thefirst to tenth times, and eleventh to twentieth times). Then, each ofthe tapes after being subjected to the tape stripping was put in alight-shielding microtube, to which 1 mL of the above-describedextractant was added. The mixture was stirred with the vortex mixer forthree hours, and the fluorescently-labeled insulin in the tape wasextracted. The YMP skin after being subjected to the tape stripping 20times was cut into small pieces (16 pieces) with a utility knife, andput into a light-shielding microtube, to which 1 mL of theabove-described extractant was added. The mixture was stirred with thevortex mixer for three hours, and the fluorescently-labeled insulin inthe skin was extracted. The extracted solution thus obtained wasfiltered using a PTFE filter (0.45 μm), and then, the quantity of thefluorescently-labeled insulin in the solution was determined using thefluorescence spectrometer LS-55 (manufactured by PerkinElmer, Inc.)(each calculated as the average value of three tests). The fluorescencespectrometer measurement was made at an excitation wavelength of 495 nmand a measurement wavelength of 521 nm. FIG. 4 illustrates the resultsobtained.

As illustrated in FIG. 4, the results were obtained, showing that thetransdermally absorbable base materials of Examples 6 and 7 surpass thetransdermally absorbable base material of Comparative Example 2 intransdermal absorption of insulin. The amount of insulin for the firstto tenth times of the stripping was high, which suggested that theinsulin penetrated to an upper layer portion of the stratum corneum.

In this way, the result shows that the transdermally absorbable basematerial of the present invention is useful as a transdermallyabsorbable base material excellent in the transdermal absorbabilitythereof when the active ingredients, such as insulin, are blendedtherewith.

Examples 10 and 11 and Comparative Example 3: Preparation ofTransdermally Absorbable Base Material Using Premix

According to Table 4 below, Phase A (premix prepared in Example 1) wasweighed out into a sample tube No. 5, and heated in a water bath (at aset temperature of 85° C.) to be uniformly dissolved.

The ingredients of Phase B were weighed out into another Maruemu sampletube No. 5 having therein a stirrer chip, and heated in a water bath (ata set temperature of 85° C.). Phase A was added to Phase B, mixed whilebeing heated and stirred for roughly 30 seconds. Then, the mixture wascooled while being stirred until the liquid temperature reached roughly60° C.

For each of Examples 10 and 11, the ingredients of Phase C were weighedout into still another sample tube No. 5, and heated to a liquidtemperature of roughly 60° C. When the liquid temperature of (PhaseA+Phase B) described above reached 60° C., Phase C having a liquidtemperature of roughly 60° C. was added thereto, and the mixture wasstirred for roughly 30 seconds, and then left at rest and cooled to beformed into a gel (transdermally absorbable base material).

For Comparative Example 3, after the liquid temperature reached roughly60° C., the mixture was left at rest and cooled to be formed into a gel(transdermally absorbable base material). Each of the preparedtransdermally absorbable base materials contains 0.1% by mass of thefluorescently-labeled insulin (FITC-labeled insulin).

TABLE 4 Exam- Exam- Comparative Ingredient (g) ple 10 ple 11 Example 3Phase A Premix 5 5 1.0 wt % Carbopol *¹⁸ 50 Phase B 0.333 wt %FITC-labeled 30 30 30 insulin aqueous solution *¹⁹ 1,3-butanediol *²⁰ 2020 IPM *²¹ 10 1M NaOH *²² 0.5 10% Tween 20 aqueous 5 solution *²³ Water35 20 19.5 Phase C 5 wt % Mg ascorbate 10 10 aqueous solution *²⁴ *¹⁸manufactured by Nikko Chemicals Co., Ltd. [product name: Carbopol 940]*¹⁹ FITC-labeled insulin prepared in Preparation Example 1 *²⁰manufactured by ITO, Inc. [product name: 13 Butimoist] *²¹ manufacturedby Tokyo Chemical Industry Co., Ltd. [product name: Isopropyl Myristate]*²² manufactured by Nacalai Tesque, Inc. [product name: 1 mol/L-sodiumhydroxide solution] *²³ manufactured by Tokyo Chemical Industry Co.,Ltd. [product name: Tween #20] *²⁴ L-ascorbic acid phosphate Mg,L-ascorbic acid phosphate ester magnesium salt manufactured by Wako PureChemical Industries Ltd.

Example 12: Skin Permeability Test of Transdermally Absorbable BaseMaterial

Yucatan Micro Pig (YMP) skin (by Charles River Laboratories Japan, Inc.)stored at −80° C. was thawed at room temperature (roughly 25° C.), andwas then subjected to the fat removal (to have a skin thickness ofroughly 2 mm). Thus, the YMP skin of roughly 2 cm square was prepared.

To a receiver phase of the vertical Franz type diffusion cell (effectivearea: 0.785 cm²), 5.0 mL of phosphate buffered saline (PBS of pH 7.4,stirred at 500 rpm) was added, and the above-described YMP skin(temperature of PBS on skin surface: 32.5° C.) was set. Each of the gels(200 mg) prepared in Examples 10 and 11 and Comparative Example 3 wasplaced in the donor phase of the vertical Franz type diffusion cell(refer to FIG. 2).

The skin was taken out after 24 hours, and washed with the extractant[solution of PBS, acetonitrile, and methanol mixed at 2:1:1 (v/v/v)].The liquid on the skin surface was wiped out with KimWipes (registeredtrademark). Then, the skin was cut into small pieces (16 pieces) with autility knife, and put into a light-shielding microtube, to which 0.5 mLof the above-described extractant was added. The mixture was stirredwith the vortex mixer for three hours, and the fluorescently-labeledinsulin in the skin was extracted. The extracted solution thus obtainedwas filtered using a PTFE filter (0.45 μm), and then, the quantity ofthe fluorescently-labeled insulin in the solution was determined usingthe fluorescence spectrometer LS-55 (manufactured by PerkinElmer, Inc.)(each calculated as the average value of three tests). The fluorescencespectrometer measurement was made at an excitation wavelength of 495 nmand a measurement wavelength of 521 nm. FIG. 5 illustrates the resultsobtained.

As illustrated in FIG. 5, the results were obtained, showing that thetransdermally absorbable base materials of Examples 10 and 11 surpassthe transdermally absorbable base material of Comparative Example 3 intransdermal absorption of insulin.

In this way, the result shows that the transdermally absorbable basematerial of the present invention is useful as a transdermallyabsorbable base material excellent in the transdermal absorbabilitythereof when the active ingredients, such as insulin, are blendedtherewith.

Moreover, the following test was conducted to examine the effect of thepolyoxyethylene lauryl ether in the premix of the present invention(Examples 13 and 14).

Example 13 and Comparative Example 4: Preparation of TransdermallyAbsorbable Base Material Using Premix

According to Table 5 below, Phase A (premix prepared in Example 1) wasweighed out into a sample tube No. 5, and heated in a water bath (at aset temperature of 85° C.) to be uniformly dissolved.

The ingredients of Phase B were weighed out into another Maruemu sampletube No. 5 having therein a stirrer chip, and heated in a water bath (ata set temperature of 85° C.). Phase A was added to Phase B, mixed whilebeing heated and stirred for roughly 30 seconds. Then, the mixture wascooled while being stirred until the liquid temperature reached roughly60° C.

The ingredients of Phase C were weighed out into still another sampletube No. 5, and heated to a liquid temperature of roughly 60° C. Whenthe liquid temperature of mixture of Phase A and Phase B described abovereached 60° C., Phase C having a liquid temperature of roughly 60° C.was added thereto, and the mixture was stirred for roughly 30 seconds,and then left at rest and cooled to be formed into a gel (transdermallyabsorbable base material).

For Comparative Example 4, the ingredients of Phase B were weighed outinto another Maruemu sample tube No. 5 having therein a stirrer chip,and heated in a water bath (at a set temperature of 85° C.). Phase B wasmixed while being heated and stirred for roughly 30 seconds, and thencooled while being stirred until the liquid temperature reached roughly60° C. After the liquid temperature reached roughly 60° C., Phase B wasleft at rest and cooled to be formed into a gel (transdermallyabsorbable base material). Each of the prepared transdermally absorbablebase materials contains 0.1% by mass of the fluorescently-labeledinsulin (FITC-labeled insulin).

TABLE 5 Exam- Comparative Ingredient (g) ple 13 Example 4 Phase A Premix5 Phase B 0.333 wt % FITC-labeled 30 30 insulin aqueous solution *²⁵1,3-butanediol *²⁶ 20 Polyoxyethylene 0.4 lauryl ether *²⁷ Water 35 69.6Phase C 5 wt % Mg ascorbate 10 aqueous solution *²⁸ *²⁵ FITC-labeledinsulin prepared in Preparation Example 1 *²⁶ manufactured by ITO, Inc.[product name: 13 Butimoist] *²⁷ Polyoxyethylene lauryl ether BL-4.23458 manufactured by Nikko Chemicals Co., Ltd. *²⁸ L-ascorbic acidphosphate Mg, L-ascorbic acid phosphate ester magnesium saltmanufactured by Wako Pure Chemical Industries Ltd.

Example 14: Skin Permeability Test of Transdermally Absorbable BaseMaterial

Yucatan Micro Pig (YMP) skin (by Charles River Laboratories Japan, Inc.)stored at −80° C. was thawed at room temperature (roughly 25° C.), andwas then subjected to the fat removal (to have a skin thickness ofroughly 2 mm). Thus, the YMP skin of roughly 2 cm square was prepared.

To a receiver phase of the vertical Franz type diffusion cell (effectivearea: 0.785 cm²), 5.0 mL of phosphate buffered saline (PBS of pH 7.4,stirred at 500 rpm) was added, and the above-described YMP skin(temperature of PBS on skin surface: 32.5° C.) was set. Each of the gels(200 mg) prepared in Example 13 and Comparative Example 4 was placed inthe donor phase of the vertical Franz type diffusion cell (refer to FIG.2).

The skin was taken out after 24 hours, and washed with the extractant[solution of PBS, acetonitrile, and methanol mixed at 2:1:1 (v/v/v)].The liquid on the skin surface was wiped out with KimWipes (registeredtrademark). Then, the skin was cut into small pieces (16 pieces) with autility knife, and put into a light-shielding microtube, to which 0.5 mLof the above-described extractant was added. The mixture was stirredwith the vortex mixer for three hours, and the fluorescently-labeledinsulin in the skin was extracted. The extracted solution thus obtainedwas filtered using a PTFE filter (0.45 μm), and then, the quantity ofthe fluorescently-labeled insulin in the solution was determined usingthe fluorescence spectrometer LS-55 (manufactured by PerkinElmer, Inc.)(each calculated as the average value of three tests). The fluorescencespectrometer measurement was made at an excitation wavelength of 495 nmand a measurement wavelength of 521 nm. FIG. 6 illustrates the resultsobtained.

As illustrated in FIG. 6, no transdermal absorption enhancing effect ofinsulin was found to be provided by 0.4% polyoxyethylene lauryl etheritself contained in the premix.

Example 15: Preparation of Premix

The Pal-GH obtained in Synthesis Example 1 above, 1,2-hexanediol,stearic acid, and water were weigh out so as to form a composition (% bymass) illustrated in Table 6, and charged into a sample tube (No. 7manufactured by Maruemu Corporation). The mixture was heated and stirredat 80° C. to obtain a Pal-GH dispersion liquid (premix). The stirringwas performed at 200 rpm using a LABORATORY HIGH MIXER manufactured byAS ONE Corporation.

This premix did not contain the surfactant, which was added when thetransdermally absorbable base material was prepared afterward.

TABLE 6 Ingredient Premix composition (% by mass) Pal-GH 6.01,2-hexanediol *²⁹ 20.0 Stearic acid *²⁹ 0.6 Water Rest *²⁹ manufacturedby Wako Pure Chemical Industries Ltd.

Examples 16 and 17 and Comparative Example 5: Preparation ofTransdermally Absorbable Base Material Using Premix

According to Table 7 below, Phase A (premix prepared in Example 15) wasweighed out into a sample tube No. 5, and heated in a water bath (at aset temperature of 85° C.) to be uniformly dissolved.

The ingredients of Phase B were weighed out into another Maruemu sampletube No. 5 having therein a stirrer chip, and heated in a water bath (ata set temperature of 85° C.). Phase A was added to Phase B, mixed whilebeing heated and stirred for roughly 30 seconds. Then, the mixture wascooled while being stirred until the liquid temperature reached roughly60° C. After the liquid temperature reached roughly 60° C., the mixturewas left standing as it was and cooled to be formed into a gel(transdermally absorbable base material). Each of the preparedtransdermally absorbable base materials contains 0.1% by mass of thefluorescently-labeled insulin (FITC-labeled insulin).

TABLE 7 Exam- Exam- Comparative Ingredient (g) ple 16 ple 17 Example 5Phase A Premix 5 5 1.0 wt % Carbopol *³⁰ 60 Phase B 0.3 wt % FITC- 34 3434 labeled insulin aqueous solution *³¹ 3 wt % propylene 10 10 glycolalginate *³² IPM *³³ 10 1M NaOH *³⁴ 0.47 10% Tween 20 5 aqueous solution*³⁵ Water 51 36 5.53 *³⁰ manufactured by Nikko Chemicals Co., Ltd.[product name: Carbopol 940] *³¹ FITC-labeled insulin manufactured bySigma-Aldrich Corporation *³² aqueous solution prepared using propyleneglycol alginate manufactured by Wako Pure Chemical Industries Ltd. *³³manufactured by Tokyo Chemical Industry Co., Ltd. [product name:Isopropyl Myristate] *³⁴ manufactured by Nacalai Tesque, Inc. [productname: 1 mol/L-sodium hydroxide solution] *³⁵ manufactured by TokyoChemical Industry Co., Ltd. [product name: Tween #20]

Example 18: Skin Permeability Test of Transdermally Absorbable BaseMaterial

Yucatan Micro Pig (YMP) skin (by Charles River Laboratories Japan, Inc.)stored at −80° C. was thawed at room temperature (roughly 25° C.), andwas then subjected to the fat removal (to have a skin thickness ofroughly 2 mm). Thus, the YMP skin of roughly 2 cm square was prepared.

To a receiver phase of the vertical Franz type diffusion cell (effectivearea: 0.785 cm²), 5.0 mL of phosphate buffered saline (PBS of pH 7.4,stirred at 500 rpm) was added, and the above-described YMP skin(temperature of PBS on skin surface: 32.5° C.) was set. Each of the gels(200 mg) prepared in Examples 16 and 17 and Comparative Example 5 wasplaced in the donor phase of the vertical Franz type diffusion cell(refer to FIG. 2).

The skin was taken out after 24 hours, and washed with the extractant[solution of PBS, acetonitrile, and methanol mixed at 2:1:1 (v/v/v)].The liquid on the skin surface was wiped out with KimWipes (registeredtrademark). Then, the skin was cut into small pieces (16 pieces) with autility knife, and put into a light-shielding microtube, to which 0.5 mLof the above-described extractant was added. The mixture was stirredwith the vortex mixer for three hours, and the fluorescently-labeledinsulin in the skin was extracted. Also, 1 mL of the receiver solutionof the Franz type diffusion cell was put into the light-shieldingmicrotube. The extracted solution thus obtained was filtered using aPTFE filter (0.20 μm), and then, the quantity of thefluorescently-labeled insulin in the solution was determined using thefluorescence spectrometer LS-55 (manufactured by PerkinElmer, Inc.)(each calculated as the average value of three tests). The fluorescencespectrometer measurement was made at an excitation wavelength of 495 nmand a measurement wavelength of 521 nm. FIG. 7 illustrates the resultsobtained.

As illustrated in FIG. 7, the results were obtained, showing that thetransdermally absorbable base materials of Examples 16 and 17 surpassthe transdermally absorbable base material of Comparative Example 5 intransdermal absorption of insulin. No difference was found in density(roughly 0.2 μg/cm²) of the fluorescently-labeled insulin in thereceiver solution.

In this way, the result shows that the transdermally absorbable basematerial of the present invention is useful as a transdermallyabsorbable base material excellent in the transdermal absorbabilitythereof when the active ingredients, such as insulin, are blendedtherewith.

Example 19: Observation of Fluorescently-Labeled Insulin Penetrationinto Mouse Ear

An ear of a mouse (Kyudo Co., Ltd.) stored at −80° C. was thawed at roomtemperature (roughly 25° C.), and was then cut out into a size ofroughly 5 mm square to serve as a specimen, to which 50 mg of the gelcontaining the Pal-GH gel premix prepared in Example 6 was added. After4 hours, the gel was removed from the specimen. Subsequently, thespecimen was placed on a glass slide, and several drops of isopropylmyristate (IPM) were dropped thereon. The specimen was covered with acover glass to form a prepared slide, and was observed with a confocalmicroscope (LSM 700 manufactured by Carl Zeiss Microscopy GmbH). Insteadof the transdermally absorbable base material, 10 μL of phosphatebuffered saline (PBS) was added to prepare a prepared slide in the sameway as a reference, which was compared with the specimen describedabove. FIG. 8 illustrates the results (in FIG. 8, Bright-field, FITC,and Merge represent a bright-field image, a fluorescence image, and acombined image thereof, respectively). From FIG. 8, a state was observedwhere the use of the transdermally absorbable base material prepared inExample 6 caused the insulin to penetrate through intracellularpathways.

Example 20: Observation of Fluorescently-Labeled Insulin Penetrationinto Mouse Ear

An ear of a mouse (Kyudo Co., Ltd.) stored at −80° C. was thawed at roomtemperature (roughly 25° C.), and was then cut out into a size ofroughly 5 mm square to serve as a specimen, to which 50 mg of the gelprepared in Example 16 was added. After 4 hours, the gel was removedfrom the specimen. Subsequently, the specimen was placed on a glassslide, and several drops of isopropyl myristate (IPM) were droppedthereon. The specimen was covered with a cover glass to form a preparedslide, and was observed with the confocal microscope (LSM 700manufactured by Carl Zeiss Microscopy GmbH). Instead of thetransdermally absorbable base material, 10 μL of phosphate bufferedsaline (PBS) was added, to prepare a prepared slide in the same way as areference, which was compared with the specimen described above. FIG. 9illustrates the results (in FIG. 9, Bright-field, FITC, and Mergerepresent a bright-field image, a fluorescence image, and a combinedimage thereof, respectively).

From FIG. 9, a state was observed where the use of the transdermallyabsorbable base material prepared in Example 16 caused the insulin topenetrate through intracellular pathways.

[Observation of Fluorescently-Labeled Insulin Penetration into YMP Skin]

Yucatan Micro Pig (YMP) skin (by Charles River Laboratories Japan, Inc.)stored at −80° C. was thawed at room temperature (roughly 25° C.), andwas then subjected to the fat removal (to have a skin thickness ofroughly 2 mm). Thus, the YMP skin of roughly 2 cm square was prepared.

To a receiver phase of the vertical Franz type diffusion cell (effectivearea: 0.785 cm²), 4.0 mL of phosphate buffered saline (PBS of pH 7.4,stirred at 500 rpm) was added, and the above-described YMP skin(temperature of PBS on skin surface: 32.5° C.) was set. Then, air in thevertical Franz type diffusion cell was removed, and 1 mL of the PBS wasadded. Then, the gel (200 mg) prepared in Example 16 was added. After 24hours, the gel was removed, and the YMP skin was subjected to permeationin a 4% paraformaldehyde fixative solution (manufactured by Muto PureChemicals Co., Ltd.) for 5 hours to be fixed. Then, the skin was placedin a plastic base mold, into which O. C. T. compound (manufactured bySakura Finetek Japan Co., Ltd.) was added to freeze the skin with liquidnitrogen. The skin was kept in a deep freezer (−80° C.). Then, a roundchuck was attached to the frozen skin, which was cut out into a frozensection having a thickness of 12 μm using a cryostat microtome, andstuck onto a prepared slide. Several drops of the PBS solution weredropped onto the prepared slide, and the O. C. T. compound was removed.Then, several drops of the PBS solution were dropped again, and a coverglass was set so as not to let air enter while the prepared slide waswet. The prepared slide was observed with a fluorescence microscope. Ascomparison, the above-described operations were performed using only aninsulin aqueous solution (containing 34 wt % of 0.3 wt % FITC-labeledinsulin aqueous solution and 66 wt % of water) (200 mg) instead of thetransdermally absorbable base material and phosphate buffered saline(PBS) as a reference, and the prepared slides were observed with thefluorescence microscope.

FIG. 10 illustrates fluorescence micrographs of the observed YMP skins(in FIG. 10, Bright-field, FITC, and Merge represent a bright-fieldimage, a fluorescence image, and a combined image thereof,respectively). It was found from FIG. 10 that the most intensefluorescence was emitted from the YMP skin to which the gel prepared inExample 16 was applied. This suggested that the insulin penetrated tothe stratum corneum.

The invention claimed is:
 1. A method of transdermally absorbing anactive component, the method comprising: applying a compositioncomprising a lipid peptide compound of Formula (1) or pharmaceuticallyusable salts thereof, a surfactant, an 1,2-alkanediol or a glycerin, atleast one fatty acid, water, and the active component to skin,

wherein R¹ is a C₉₋₂₃ aliphatic group; R² is a hydrogen atom or a C₁₋₄alkyl group that optionally has a branched chain having a carbon atomnumber of 1 or 2; R³ is a —(CH₂)—X group; n is a number of 1 to 4; and Xis amino group, guanidino group, —CONH₂ group, or a 5-membered cyclicgroup optionally having 1 to 3 nitrogen atoms, a 6-membered cyclic groupoptionally having 1 to 3 nitrogen atoms, or a condensed heterocyclicgroup constituted by a 5-membered cyclic group and a 6-membered cyclicgroup which optionally have 1 to 3 nitrogen atoms; wherein the activecomponent is selected from hyaluronic acid and insulin, wherein the atleast one fatty acid is selected from among the group consisting ofcapric acid, myristic acid, palmitic acid, and stearic acid, and whereinthe surfactant is at least one of an ethylene glycol alkyl ether, aphospholipid, and a polyglycerin fatty acid ester; and allowing theactive component to transdermally absorb into the skin.
 2. The methodaccording to claim 1, wherein in Formula (1), R¹ is a linear aliphaticgroup having a carbon atom number of 15, R² is a hydrogen atom, and R³is 4-imidazole methyl group.